Annual Report 2012 Annual Report

FIMM Annual Report 2012 Annual Report

ANNUAL REPORT 2012

www.fimm.fi • P.O. Box 20, FI-00014 University of Helsinki, Finland • Biomedicum Helsinki 2U, Tukholmankatu 8, 00290 Helsinki, Finland Editors: Olli Kallioniemi, William Hennah, Mari Kaunisto, Marja Medina, Reetta Niemelä, Gretchen Repasky, Susanna Rosas, Jouko Siro, Tiina Vesterinen

Photos and graphics: Jouko Siro, Masha Anastasina, Lise Balsby, Sami Blom, Jason DeBose, Oxana Denisova, Henrik Edgren, Samuel Eldfors, Caroline Heckman, William Hennah, Wilma Hurskainen, Harri Itkonen, Mari Kaunisto, Siv Knaappila, Sergey Kuznetsov, Kari Likonen, Michel Mees, Muntasir Mamun Majumder, Ruusu-Maaria Merivirta, Timo Miettinen, John Patrick Mpindi, Katja Närhi, Tea Pemovska, Aleksi Poutanen, Maija Puhka, Gretchen Repasky, Mikko Sallinen, Veikko Somerpuro, Rauno Träskelin, Tiina Vesterinen

Academy of Finland, EATRIS, European Molecular Biology Laboratory (EMBL), Finnish Red Cross Blood Service and University of Helsinki are acknowledged for the photos.

Juvenes Print 2013

Contents

Director’s overview...... 4 The first fiveears y at FIMM...... 6 Nordic EMBL Partnership for Molecular Medicine expanded to Denmark...... 8 Greetings...... 9 Bridge-building towards the clinic...... 9 Chair of the Board of FIMM...... 10 Former Chair of the Board of FIMM, Vice President for Research, Academy of Finland ...... 10 Chancellor of the University of Helsinki...... 11 Grand Challenges...... 12 Individualized Systems Medicine (ISM) for accelerating translational oncology in AML...... 12 Utilizing Finnish Genomes to empower personalised and predictive health...... 13 Research Highlights...... 14 Research Groups in Human Genomics...... 18 Group Palotie...... 19 Group Hennah...... 21 Group Palmgren...... 22 Group Ripatti...... 23 Group Saarela...... 24 Group Widen...... 25 Research Groups in Systems Medicine and Translational Research...... 26 Group Kallioniemi...... 26 Group Aittokallio...... 27 Group Kainov...... 28 Group Knowles...... 29 Group Kuznetsov...... 30 Group Lundin...... 31 Group Verschuren...... 33 Group Wennerberg...... 34 Finland Distinguished Professors at FIMM...... 35 Doctoral Training...... 36 Technology Centre...... 39 Biobanking...... 46 Administration...... 52 Examples of On-going Projects...... 55 A year at FIMM...... 59 FIMM in Figures...... 64 Publications 2012 ...... 68

FIMM • 3 Director’s overview

hen starting as the Director of FIMM in December W2007, I was asked to prepare a plan for the development of the new institute as part of the Nordic EMBL Part- nership for Molecular Medicine. The following is an excerpt from these plans: “Molecular medicine of the future needs to focus on personalised medicine, making use of molecular data at the level of the individual patient to drive diagnostic and therapeutic decisions. FIMM represents a unique opportunity to advance molecular medicine in Finland. The focus and mission should revolve around translational research, i.e. taking advantage of the high-quality biomedical discoveries in Finland to advance personalised medicine in the decades to come”. Everything above is still very true as we now venture towards the next 5-year period. However, as compared to the 2007, we now have almost 200 people, 15 group leaders, a strong Technology Centre and Biobanking Infrastructure to help realize such goals. Significant progress towards scientific breakthroughs and personalised medicine Photo by Michel Mees has happened and much more is now underway. EATRIS is credited for the photo.

FIMM was awarded an excellent start-up funding to recruit sources, about 10 M€/year in 2012–2013. The science pol- EMBL-style group leaders and to launch a new institute. The icy in Finland is designed such that the research commu- support from Jane and Aatos Erkko Foundation, Sigrid Jusé- nity is dependent on a continuous supply of competitive lius Foundation, The Finnish Medical Foundation, Orion- external grants. While FIMM researchers have been very Farmos Research Foundation, the City of Helsinki, Ministry successful in acquiring such funding, this will not serve as of Education and Culture, the University of Helsinki and the a replacement for basic funding. Therefore, our ability to Hospital District of Helsinki and Uusimaa (HUS) is gratefully operate an EMBL-style molecular medicine institute with acknowledged. This annual report is a testimony to what rotating group leader positions is far from certain in this has been achieved in the past five years. The start-up fund- scenario. Like any other institute under the University of ing helped to build an institute and recruit an excellent group Helsinki umbrella, FIMM has to rely largely on competitive of young talented investigators at all levels, from PIs to PhD national and international project funding for its support. students. Due to everybody’s dedicated work, FIMM is now This is not quite like the EMBL model, where recruitment of established in the international arena as an expert site for international top talent to rotational 5+4 year PI-positions human genomics and personalised medicine research, with with good basic support is a key feature. Also, term-limited groundbreaking translational and clinical capabilities. grant support is not optimal for running long-term high- risk and ambitious research goals of societal importance. The FIMM start-up funding is now ending in 2013–2014. As a result of the University Reform Act in 2009, the future of With these challenges on the future in mind, what is the FIMM will remain largely dependent on the basic funding FIMM strategy for the future? We remain committed to support from its primary host, the University of Helsinki. carry out high-quality research and to translate these to Since the budgets for universities are not increasing, it is the clinic. We believe that an important way to achieve this very difficult for the University to assume responsibility for will be to focus strongly on grand challenges in the socie- all the work previously supported by the start-up funds at ty, and make almost the entire institute to work together FIMM. Therefore, most likely the total support for FIMM re- towards such goals. We have two established and one search will go down in 2014–2015. Fortunately, FIMM has emerging grand challenge initiatives under development at acquired significant external project funding from diverse FIMM. The first one involves the application of Finnish ge-

4 • FIMM nome information for the development of personalised and predictive health care. The second one involves the development of the concept of individualized systems medicine for cancer care, starting from acute leukaemias. The third grand challenge involves digital image-based pathological diagnostics, which will be required as we move molecular pathology towards multiplexed in situ assays, quantitative assays and automatic decision support. Taken together, we believe that these three grand challenges will help to refine the institutes’ mission. In 2020, we hope to have contributed to a national policy that enables Finland to be a leading country in the implementation of personalised medicine in health care at the level of the citizens, primary care, secondary care, both public and private.

Professor Olli Kallioniemi, Director, FIMM

Orion-Farmos Research Foundation

FIMM • 5 The first five years at FIMM

2007 2008 2009 2010 2011 2012 2013 2014 2020

FiDiPro Professor Jonathan Knowles

FIMM-EMBL Group Leaders Krister Wennerberg and Samuli Ripatti

FIMM Clinical Collaboration Programme

FIMM-EMBL PhD International Training Initiative

Biomedinfra (national ESFRI collaboration) FiDiPro Professor Leif Groop

PREDECT (Innovative Medicine Initiative) BBMRI-LPC project

Biocenter Finland funding Olli Kallioniemi EU-OPENSCREEN project appointed Janna Saarela appointed Research Director of Director, FIMM Technology Centre FIMM 2012-2017 FiDiPro Professor Juni Palmgren Aarno Palotie FIMM-EMBL Group Leaders Emmy appointed Research FIMM-EMBL Group Leader Verschuren and Denis Kainov Director, FIMM Tero Aittokallio Personnel Human Genomics 200 FIMM National Network Johan Lundin appointed Research for Molecular Medicine Director, Diagnostic Development

First FIMM-EMBL Group Leader Sergey Kuznetsov

150 EATRIS project

ENGAGE project Vision: 2020 FIMM is an international 2002: The idea to establish Academy Professor Olli leading centre for 100 an international molecular Kallioniemi appointed ﬁrst medicine research centre Director of FIMM 2007-2012 molecular medicine and in the Nordic countries. Finland is a leading Academy Professor Leena country in personalised Peltonen-Palotie appointed medicine. Research Director of FIMM Human Genomics 50

2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2020

Initiative of the Academy Decision on the VTT joined FIMM THL established New University Law International Evaluation of Renewal and expansion of of Finland to establish establishment of (KTL and Stakes Research and Doctoral Training at the Nordic EMBL Partnership for a research centre in FIMM by the Senate merged) the University of Helsinki 2005-2010 Molecular Medicine 2013-2023 Finland with EMBL of the University of Biomedicum FIMM Launch Helsinki as a joint Helsinki 2U building Event and SAB Visit institute of Academician of Science Leena SAB Visit and FIMM 5-year Evaluation the University, The Board of FIMM Peltonen-Palotie Memorial Report of the Biotechnology HUS and KTL The Board and SAB of FIMM nominated nominated 2010-2014 Symposium 2005 Expert Group of the Ministry of Education Finnish Genome Start-up funding from the Ministry of SAB Visit Centre merged Education (2007-2009), Erkko, Jusélius, to FIMM Finnish Medical and Orion-Farmos Foundations, the City of Helsinki and HUS

Establishment of the Nordic EMBL Partnership for Molecular Medicine 2007-2012 6 • FIMM 2007 2008 2009 2010 2011 2012 2013 2014 2020

FiDiPro Professor Jonathan Knowles

FIMM-EMBL Group Leaders Krister Wennerberg and Samuli Ripatti

FIMM Clinical Collaboration Programme

FIMM-EMBL PhD International Training Initiative

Biomedinfra (national ESFRI collaboration) FiDiPro Professor Leif Groop

PREDECT (Innovative Medicine Initiative) BBMRI-LPC project

First FIMM-EMBL Group Leader Sergey Kuznetsov

150 EATRIS project

2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2020

Establishment of the Nordic EMBL Partnership for Molecular Medicine 2007-2012 FIMM • 7 Nordic EMBL Partnership for Molecular Medicine expanded to Denmark

The Nordic EMBL Partnership for Molecular Medicine expanded to Denmark as the agreement between EMBL, DANDRITE, Aarhus University, FIMM, University of Helsinki, MIMS, Umeå University and NCMM, University of Oslo was signed on 5 March 2013 in Aarhus, Denmark. The Agreement for Establishing the Nordic EMBL Partnership was initially signed in 2007 for a five-year period. Now the agreement was renewed for a ten-year period. Rector Thomas Wilhelmsson and Director Olli Kallioniemi signed the agreement on behalf of FIMM, University of Helsinki.

“When establishing the Nordic EMBL Partnership in 2007, the idea was to promote synergistic collaboration between the Nordic countries and EMBL. The Partnership has achieved its goals.” stated Director General of EMBL, Professor Iain Mattaj in Aarhus. He also found it important that the collaboration is based on national strengths of the four Nordic countries and that the research focus areas in the nodes are complementary in nature.

“The Nordic EMBL Partnership provides an excellent platform for Nordic and European research and infrastructure collaboration. In addition, joint training initiatives and mobility of researchers can be supported in many ways within this institutional and coordinated Partnership.” said Rector Thomas Wilhelmsson. DANDRITE (Danish Research Institute of Translational Neuroscience) started in January 2013 with three core groups of Professors Poul Nissen (Interim Director), Anders Nykjaer and Poul Henning Jensen. Altogether five EMBL style selected group leaders will be recruited to the Institute. In addition to Aarhus University, the Lundbeck Foundation is committed to fund DANDRITE for a ten-year period.

Photos by Lise Balsby

8 • FIMM Greetings

Bridge-building towards the clinic

Cancer diagnostics and treatments have changed substantially during the last several years. No longer are all cancers considered to behave similarly in all patients. Instead, a more precise diagnostic workup is anticipated to reveal different subcategories for different cancer types. All this aims at optimized patient outcome as treatments can be individualized.

This personalised approach to cancer diagnostics and treatments is to a large extent driven by a fast development of laboratory technologies. Not only have techniques like next-generation sequencing become cheaper and faster, but also novel and exciting technologies such as high-throughput drug testing and automated image analysis are around the corner.

To eventually utilize these techniques in patient care, thorough translational research needs to be conducted. In this respect, the natural collaborator for a clinician in Helsinki University Central Hospital (HUCH) is FIMM, with its impressive infrastructure and innovative research groups.

A good example of successful collaboration is individualized treatment of Acute Myeloid Leukaemia (AML) patients using Drug Sensitivity and Resistance Testing (DSRT) technology in a joint program between Division of Hematology at HUCH and FIMM. This programme is backed up by an ambitious national biobanking protocol set up between the Finnish Association of Hematology and FIMM (http://www.hematology.fi/fhrb).

A similar approach is used for urologic solid organ tumours, also backed up by a collaborative biobanking protocol between Department of Urology at HUCH and FIMM with impressive 600 patient consents and more that 10.000 sample aliquots collected after the first year of operation only (http://www.hubbiobank.fi/en/).

Professor Kimmo Porkka and Docent Antti Rannikko, University of Helsinki and Helsinki University Central Hospital (HUCH)

FIMM • 9 Chair of the Board of FIMM

The year 2012 concluded the five-year (2008—2012) start-up and construction phase of FIMM. During this period, FIMM has become an international high-profile research institute in molecular medicine research, with world-class infrastructure, focus towards creating tangible benefits to the society and applications linking top-class medical research with industrial collaboration.

The results of the International Evaluation of Research and Doctoral Training of the University of Helsinki 2005—2010 were published in 2012. FIMM researchers were involved in three Researcher Communities: Cancer Biology (CANBIO), Complex Disease Genomics Group (CompDisGen) and Personalised Molecular Medicine (P-Molmed). All of these received top scores, with the P-Molmed receiving the highest ranking score in the category for societal impact.

In 2012, based on the recommendations of the Scientific Advisory Board (SAB) and Board of FIMM, Rector Thomas Wilhelmsson appointed Professor Olli Kallioniemi the Director of FIMM for another five-year term, starting in December 2012. Olli Kallioniemi’s Inauguration Lecture “Personalised Medicine 2020” took place in January 2013.

Together with Rector Thomas Wilhelmsson and the Board of FIMM, we have carefully discussed the FIMM funding situation in the forthcoming years. International recruitment of global experts to Finland has been implemented with internationally competitive support packages (about 1.5 M€/group leader/five years) during the first five-year period, by virtue of valuable support from several private foundations and the University of Helsinki. FIMM researchers have been successful in competition of external project funding. However, maintenance of EMBL group leader salaries and attractive long-term start-up packages cannot be covered by external project funding only. Acquisition of sustainable funding to maintain the EMBL status remains a challenging, but reachable, task in the future.

Professor Kimmo Kontula, Vice Rector of the University of Helsinki, Chair of the Board of FIMM 2010—2014

Former Chair of the Board of FIMM, Vice President for Research, Academy of Finland

The European Molecular Biology Laboratory (EMBL) was founded in 1974 as an inter- governmental institute to initiate in Europe research in the then new field, molecular biology. Today, EMBL is one of the world’s leading institutes in the life sciences, funded by 20 Member States and operating in its headquarters in Heidelberg and four outstations, embracing four partnerships. One of the latter is the Nordic EMBL Partnership for Molecular Medicine, established in 2007, between EMBL, the Institute for Molecular Medicine Finland (FIMM) in Helsinki, the Centre for Molecular Medicine Norway (NCMM) in Oslo and the Laboratory for Molecular Infection Medicine Sweden (MIMS) in Umeå. The high quality health care systems, population-based registers, and patient and sample databases in the Nordic countries provide the unique niche for this collaboration. In March 2013, the Nordic EMBL Partnership was extended by a most welcome new member, the Danish Research Institute of Translational Neuroscience (DANDRITE) in Aarhus. The strengthening of the Nordic EMBL Partnership could not be timelier, as the Nordic Council of Ministers is in the process of considering opening up of research and funding opportunities and access to infrastructure across the borders of Denmark, Finland, Iceland, Norway and Sweden. The Nordic EMBL Partnership is optimally placed to further and take advantage of collaboration not only in the Nordic countries, but also to bridge it with research activities, funding opportunities and infrastructure at the European level.

Professor Marja Makarow, Vice President for Research, Academy of Finland (Vice Rector of the University of Helsinki 2003—2007; Chief Executive of the European Science Foundation 2008—2011; Chair of the Board of FIMM 2007—2010)

10 • FIMM Chancellor of the University of Helsinki

In spring 2006, the Ministry of Education and Culture (then, the Ministry of Education) commissioned the University of Helsinki to begin preparatory work to establish a research institute for molecular medicine as a joint undertaking with other biocentre universities, as well as with other institutions in the field. Background for the assignment was the initiative of an expert group of the Academy of Finland and the Biotechnology 2005 committee report of the Ministry of Education. After some negotiations, the other biocentre universities decided not to join to the institute. As the Rector of the University of Helsinki, I chaired the University Senate meeting in autumn 2006 which decided to establish the Institute for Molecular Medicine Finland (FIMM) as a joint effort of the University, the Hospital District of Helsinki and Uusimaa (HUS), and the National Institute for Health and Welfare (THL, then the National Public Health Institute, KTL). VTT Technical Research Centre of Finland joined FIMM in 2008. The Agreement for Establishing the Nordic EMBL Partnership for Molecular Medicine was signed in Heidelberg in 2007.

Today, I am happy to see that only five years after its establishment, FIMM is a highly successful international institute with a clearly defined profile in basic and translational research, with highly qualified doctoral students, researchers, group leaders and Finland Distinguished Professors, and with a world-class research infrastructure and nation-wide and international technology services. FIMM has fully accomplished the objectives set in the reports initiating the establishment of the institute.

Professor Ilkka Niiniluoto, Chancellor of the University of Helsinki (Rector of the University of Helsinki 2003—2008)

EMBL signing ceremony in 2007. EMBL is credited for the photo.

FIMM • 11 Grand Challenges

Individualized Systems Medicine (ISM) for accelerating translational oncology in AML

We have established a close collaboration with hematologists at the Helsinki University Central Hospital (HUCH) to develop a novel Individualized Systems Medicine (ISM) strategy for translational cancer research. We combine biobanking, state-of-the-art genomic technology, high-throughput drug testing, and rapid clinical translation in a programme that has grown into a major effort at FIMM and HUCH. We selected adult Acute Myeloid Leukaemia (AML) as the primary target of our studies due to its lower complexity as compared to solid tumours. Millions of cells can be readily obtained for both molecular and ex vivo drug response studies. Sampling at the time of diagnosis, remission and relapse and drug resistance is easily accomplished. Indeed, analysis of temporal evolution patterns in individual patients represents the unique opportunity. AML patients, particularly those with treatment-refractory disease with less than 10% long-term survival expectation, desperately need new therapeutic options to replace the 30–50 year-old chemotherapeutic regimens. Refractory AML therefore represents an ideal indication to introduce individualized treatments to improve cancer care. ISM combines multiple levels of medical, technological, scientific, and strategic aspects to practice translational cancer medicine as follows:

• Focus on individual patients: We will seek to understand and interpret the unique genomic and molecular profile of the disease in each individual patient. • Direct prediction of response to all drugs: Functional, large-scale drug response data are acquired from ex vivo primary culture of cancer cells from patients. • Real-time science: Biobanking, profiling, analysis, and interpretation of each case in 1–4 weeks, with feedback to the clinician. Scientists work in parallel with clinical developments one case at-a-time. • Consecutive sampling from different stages of cancer evolution: Understanding of mechanisms of drug resistance and cancer evolution for each patient. • Integration of in vivo, ex vivo and in vitro data: Model systems will be designed to understand mechanisms and causalities, such as drug combinations, based on ex vivo data from patient samples. Thus patient samples and models are compared to one another. • Implementation: Patient consent and ethical permission allow implementation of actionable results in the clinic at a time when no other therapy options exist. • Drug combinations: We will identify synergistic drug regimens blocking multiple cancer subclones and “escape routes” for cancer cells. • Systems medicine strategy: Continuous circle of (re)analysis of data and improving models and understanding: learning from each patient and each consecutive sample. • De-risking clinical trials: ISM is likely to help choose the right patients and new drugs for clinical trials.

12 • FIMM Utilizing Finnish genomes to empower personalised and predictive health

The Human Genomics Programme at FIMM builds on a long Finnish tradition of high-impact genetic research. Finland was one of the first countries to embrace advances of molecular genetics already in the 1990s, leading to the identification of mutations causing the “Finnish disease heritage”. More recently, during the past three years, FIMM researchers have with 44 publications in top medical journals, e.g. Science, Nature, Nature Genetics, Lancet, importantly contributed to the recent discoveries of novel genes and gene loci that underlie common disease.

Right now, the rapidly increasing capacity to describe the complete genetic and molecular makeup of an individual is changing the way we understand and treat disease. We foresee that Finland has a unique opportunity to be at the forefront of this developing field. To meet this upcoming grand challenge and opening, our strategy is to work towards building a platform that integrates genomic and health outcome data from Finnish national population biobanks into a globally unique and valuable “big data” repository. This plan relies on a close collaboration between FIMM and THL, but also on extensive multidisciplinary collaborations with other national stakeholders, e.g. VTT, the University of Eastern Finland, the Health & Technology Center in Oulu, the Finnish Medical Society Duodecim, the City of Helsinki and Kymenlaakso Social and Health Services and international cutting edge scientists and institutions, such as the Wellcome Trust Sanger Institute, Broad Institute and UCLA.

We envision that data mining of such a massive health data resource will facilitate predictive and preventive approaches, catalyze innovations in health care, as well as empower individuals to reach out towards better health. In our vision, patients and people are seen as active participants and drivers of a “health care system 2.0”.

FIMM • 13 Research Highlights

Mutation in the STAT3 gene identified as the cause for LGL leukaemia

Large granular lymphocytic (LGL) leukaemia is a relatively rare, malignant blood disease of the mature T-cells and, in many cases, it is related to autoimmune diseases such as rheumatoid arthritis. The pathogenetic mechanism of the disease has been unknown. Utilizing the latest DNA sequencing methods that can examine the entire genome, the research groups investigated if the LGL leukaemia cells carry mutations that would explain the onset of the disease. It was discovered that patients suffering from LGL leukaemia have a mutation in the STAT3 gene in a very restricted SH2 area, which has a key effect on the function of the gene. In the future, this result can be utilized in diagnosing the disease and possibly also in treatment, since the first STAT3 inhibitors are already undergoing early clinical trials. The cooperation project of the Meilahti campus research groups was led by Satu Mustjoki, Adjunct Professor (University of Helsinki/HUCH), together with FIMM’s researchers Caroline Heckman, Ph.D., and Olli Kallioniemi, Professor, in addition to Kimmo Porkka, Professor, Chief Physician at the Division of Hematology (HUCH).

Koskela HL, Eldfors S, Ellonen P, van Adrichem AJ, Kuusanmäki H, Andersson EI, Lagström S, Clemente MJ, Olson T, Jalkanen SE, Majumder MM, Almusa H, Edgren H, Lepistö M, Mattila P, Guinta K, Koistinen P, Kuittinen T, Penttinen K, Parsons A, Knowles J, Saarela J, Wennerberg K, Kallioniemi O, Porkka K, Loughran TP Jr, Heckman CA, Maciejewski JP, Mustjoki S. Somatic STAT3 mutations in large granular lymphocytic leukemia. N Engl J Med. 2012 May 17;366(20):1905-13.

A Multi-Omic Study Highlights the Link between Inflammation and Low HDL-C

We have performed the first genome-wide association analysis on low HDL-C. By combining genomic data with adipose tissue transcriptome and HDL particle lipidome analyses, we provide important insights into HDL biology. We show that genetic variants within inflammatory pathways are associated with low HDL-C. These variants also regulate both adipose tissue and vascular inflammation, suggesting a genetic link between inflammation and low HDL-C. We also demonstrate that not only the quantity but also the quality differs in HDL particles between subjects with low and high HDL-C; antioxidative lipid species are less abundant in HDL particles of subjects with low HDL-C highlighting the importance of distinguishing HDL particles from HDL-cholesterol when relating HDL with cardiovascular risk and atherosclerosis. Importantly, we show the value of using extreme phenotypes in genetic analysis: there are genes, especially in the HLA region, which are not associated with HDL-C in general, but only with extreme HDL-C phenotypes. This observation suggests the presence of “low/high HDL-C genes” in addition to the “HDL-C genes” that have been reported in population-based GWA studies. This paper was selected the “publication of the week” by the Faculty of Medicine, University of Helsinki.

Laurila PP, Surakka I, Sarin AP, Yetukuri L, Hyötyläinen T, Söderlund S, Naukkarinen J, Tang J, Kettunen J, Mirel DB, Soronen J, Lehtimäki T, Ruokonen A, Ehnholm C, Eriksson JG, Salomaa V, Jula A, Raitakari OT, Järvelin MR, Palotie A, Peltonen L, Oresic M, Jauhiainen M, Taskinen MR, Ripatti S. Genomic, Transcriptomic, and Lipidomic Profiling Highlights the Role of Inflammation in Individuals With Low High-density Lipoprotein Cholesterol. Arterioscler Thromb Vasc Biol. 2013 Feb 14. [Epub ahead of print] PubMed PMID: 23413431.

14 • FIMM A quantitative tool for strand-specific mRNA expression analysis

Primer-independent cDNA synthesis during reverse transcription hinders quantitative analysis of bidirectional mRNA in eukaryotes as well as in cells infected with RNA viruses. We have developed a simple RT-PCR-based assay for strand-specific gene- expression analysis. By modifying the cDNA sequence during reverse transcription, using specially designed primers, the opposite strands of target sequences can be simultaneously detected by postamplification melting curve analysis and primer- initiated transcripts are readily distinguished from nonspecifically primed cDNA. We have demonstrated the utility of this technique for analysis of (+) and (-) RNA synthesis of influenza A virus in infected cells. This technique represents a powerful tool for analysis of bidirectional RNA synthesis and it can also be utilized for monitoring primer-independent cDNA synthesis during reverse transcription. The technique was highlighted in “Biotechniques 2012 year in review” as number one of the best PCR methods published in the journal during the year.

Feng L, Lintula S, Ho TH, Anastasina M, Paju A, Haglund C, Stenman UH, Hotakainen K, Orpana A, Kainov D, Stenman J. Technique for strand-specific gene-expression analysis and monitoring of primer-independent cDNA synthesis in reverse transcription. Biotechniques. 2012 Apr;52(4):263-70.

Genome-wide association study reveals genetic loci predisposing to the most common form of migraine

By analysing close to 5,000 migraneurs and 7,200 controls by genome-wide association, we identified four gene loci predisposing to the most common form of migraine, migraine without aura. The pathophysiology of migraine is poorly understood. Identification of genes that contribute to the disease susceptibility should improve our understanding of basic disease mechanisms.

Freilinger T, Anttila V, de Vries B, Malik R, Kallela M, Terwindt GM, Pozo-Rosich P, Winsvold B, Nyholt DR, van Oosterhout WP, Artto V, Todt U, Hämäläinen E, Fernández-Morales J, Louter MA, Kaunisto MA, Schoenen J, Raitakari O, Lehtimäki T, Vila-Pueyo M, Göbel H, Wichmann E, Sintas C, Uitterlinden AG, Hofman A, Rivadeneira F, Heinze A, Tronvik E, van Duijn CM, Kaprio J, Cormand B, Wessman M, Frants RR, Meitinger T, Müller-Myhsok B, Zwart JA, Färkkilä M, Macaya A, Ferrari MD, Kubisch C, Palotie A, Dichgans M, van den Maagdenberg AM: International Headache Genetics Consortium. Genome-wide association analysis identifies susceptibility loci for migraine without aura. Nat Genet. 2012 Jun 10;44(7):777-82.

The genetics of pubertal growth

Growth patterns during puberty correlate with pubertal timing, and variability in pubertal timing associates with health risks later in life, for example for hormone- dependent cancers and adverse cardiovascular health. Although there is mounting evidence for these links, few studies have addressed the genetics of distinct phases of childhood growth. With access to over 18,000 study subjects with multiple height measurements from childhood and adolescence within the Early Growth Genetics Consortium, we identified ten loci associated with height growth during the pubertal growth spurt. Among these loci, LIN28B exemplifies a gene which may mediate the link between pubertal development and health risks later in life, as it is a gene known to influence childhood growth, pubertal timing, and cancer progression and prognosis. We also identified a novel growth and pubertal timing locus that influenced expression of the gene MAPK3, also involved in several forms of cancer. Finally, while epidemiological studies suggest that early puberty marks a pathway

FIMM • 15 from rapid prepubertal growth to reduced final height and adult obesity, we show that this is not always the case for individual genetic variants. Our study shows that tracking the genetic effects of individual genes across multiple growth periods may help uncover specific pathways linking childhood events to adult outcomes.

Cousminer DL, Berry DJ, Timpson NJ, Ang W, Thiering E, Byrne E, Taal HR,Huikari V, Bradfield JP, Kerkhof M, Groen-Blokhuis MM, Kreiner-Møller E,Marinelli M, Holst C, Leinonen JT, Perry JR, Surakka I, Pietiläinen O, Kettunen J, Anttila V, Kaakinen M, Sovio U, Pouta A, Das S, Lagou V, Power C, Prokopenko I, Evans DM, Kemp JP, St Pourcain B, Ring S, Palotie A, Kajantie E, Osmond C, Lehtimäki T, Viikari JS, Kähönen M, Warrington NM, Lye SJ, Palmer LJ, Tiesler CM, Flexeder C, Montgomery GW, Medland SE, Hofman A, Hakonarson H, Guxens M, Bartels M, Salomaa V; The ReproGen Consortium, Murabito J, Kaprio J, Sørensen TI, Ballester F, Bisgaard H, Boomsma DI, Koppelman GH, Grant SF, Jaddoe VW, Martin NG, Heinrich J, Pennell CE, Raitakari O, Eriksson JG, Smith GD, Hyppönen E, Järvelin MR, McCarthy MI, Ripatti S, Widén E; for the Early Growth Genetics (EGG) Consortium. Genome-wide Association and Longitudinal Analyses Reveal Genetic Loci Linking Pubertal Height Growth, Pubertal Timing, and Childhood Adiposity. Hum Mol Genet. 2013 Feb 27. [Epub ahead of print]

Large population cohort studies reveal that saccular intracranial aneurysms and systolic blood pressure share genetic components

Some 3% of the general population develop saccular intracranial aneurysms, the rupture of which is a major cause of life threatening subarachnoid haemorrhage. The basic mechanisms of aneurysm formation and their rupturing are poorly understood, but blood pressure is a well-known risk factor. Using well characterized Finnish population cohorts we demonstrate that one aneurysm susceptibility gene locus is associated with systolic blood pressure suggesting that these two traits have shared genetic components, possibly eluting to a shared disease mechanism.

Gaál EI, Salo P, Kristiansson K, Rehnström K, Kettunen J, Sarin AP, Niemelä M, Jula A, Raitakari OT, Lehtimäki T, Eriksson JG, Widen E, Günel M, Kurki M, von Und Zu Fraunberg M, Jääskeläinen JE, Hernesniemi J, Järvelin MR, Pouta A; The International Consortium for Blood Pressure Genome-Wide Association Studies (ICBP-GWAS), Newton-Cheh C, Salomaa V, Palotie A, Perola M: Intracranial Aneurysm Risk Locus 5q23.2 Is Associated with Elevated Systolic Blood Pressure. PLoS Genet. 2012 Mar;8(3):e1002563.

Harnessing anticancer drugs for the future fight against influenza

Influenza viruses cause significant human morbidity and mortality. To treat the infections, different virus-directed drugs have been developed. However, the currently available drugs are targeting viral proteins and due to a high mutation rate the influenza viruses quickly develop resistance to them. For that reason, next- generation antiviral drugs should be directed towards the host functions. In this work, we developed a new cell screening method that can be used to identify potential anti- influenza drugs and identified two novel compounds with anti-influenza activity. The results of this study provide a foundation for development of next-generation antiviral drugs. Furthermore, these identified compounds can be used as chemical tools when studying the molecular mechanisms of virus-host interactions.

Denisova OV, Kakkola L, Feng L, Stenman J, Nagaraj A, Lampe J, Yadav B, Aittokallio T, Kaukinen P, Ahola T, Kuivanen S, Vapalahti O, Kantele A, Tynell J, Julkunen I, Kallio-Kokko H, Paavilainen H, Hukkanen V, Elliott RM, De Brabander JK, Saelens X, Kainov DE. Obatoclax, saliphenylhalamide, and gemcitabine inhibit influenza a virus infection. J Biol Chem. 2012 Oct 12;287(42):35324-32.

16 • FIMM Metabolic signatures of insulin resistance in young adults

Insulin resistance is a core defect in the development of type 2 diabetes. Already in young adults, insulin resistance is associated with an adverse lipid profile and increased risk for future diabetes. To elucidate metabolic pathways underlying the pathogenesis of insulin resistance, we comprehensively characterized systemic metabolite profiles in over 7,000 apparently healthy young adults. We identified a diverse metabolic signature with insulin resistance beyond the conventional characteristics of obesity and dyslipidemia. A combination of amino acids, lipids, and intermediates of glycolysis formed sex-specific imprints of insulin resistance on the metabolite profile already in early adulthood. Although genetic evidence did not provide suggest a causal role of the metabolites in the development of insulin resistance, these metabolites may still help to identify individuals at high risk for progression towards future diabetes. Understanding the relation between insulin resistance and the systemic metabolite profile in young, healthy adults may help to promote lifestyle habits for prevention of insulin resistance prior to overt diabetes.

Würtz P, Mäkinen VP, Soininen P, Kangas AJ, Tukiainen T, Kettunen J, Savolainen MJ, Tammelin T, Viikari JS, Rönnemaa T, Kähönen M, Lehtimäki T, Ripatti S, Raitakari OT, Järvelin MR, Ala-Korpela M. Metabolic signatures of insulin resistance in 7,098 young adults. Diabetes. 2012 Jun;61(6):1372-80.

New computational strategies combine different omics data and identify susceptibility genes for common traits and help to construct disease networks

New methods to analyse large, omics datasets provide opportunities to improve our understanding of disease mechanisms and construct disease networks. We have combined GWAs and expression data in a multivariant model and demonstrate the power of this strategy to improve the analysis of large genome datasets.

Inouye M, Ripatti S, Kettunen J, Lyytikäinen LP, Oksala N, Laurila PP, Kangas AJ, Soininen P, Savolainen MJ, Viikari J, Kähönen M, Perola M, Salomaa V, Raitakari O, Lehtimäki T, Taskinen MR, Järvelin MR, Ala-Korpela M, Palotie A, de Bakker PI: Novel Loci for metabolic networks and multi-tissue expression studies reveal genes for atherosclerosis. PLoS Genet. 2012 Aug;8(8):e1002907.

FIMM • 17 Research Groups in Human Genomics

ased on the recommendations of the Scientific Advisory Board (SAB) and Board of FIMM Dr. Aarno Palotie was appointed BResearch Director in the field of Human Genomics in November 2012 (part-time position). Aarno Palotie is a former Director of the Finnish Genome Center. He has been one of the leaders of Human Genomics at FIMM during the last two years, while his main affiliation has been at the Wellcome Trust Sanger Institute in UK. FIMM will increasingly focus on the bioinformatic integration of genomics and other omics data with health care information, as well as on the implementation of genomics in health care. Dr. Palotie is committed to lead these Finnish grand challenge initiatives on genomes and health. “In collaboration with our national and international partners, we aim to capitalize on Finland’s unique population structure and decades of investments in epidemiological and clinical cohorts. Our goal is to make Finland the poster child of genomic medicine.” he said. Dr. Palotie is also hosting FiDiPro Professor Leif Groop’s project “Using the unique knowledge of the genetics architecture of Finland to identify the genetic variants which explain the inherited risk of diabetes”.

18 • FIMM Group Palotie Genomics and Health

Research Director, Professor Aarno Palotie, MD, PhD

he overall aim of our group is to build towards a more comprehensive understanding Tof the genomic landscape of common diseases utilizing the special opportunities provided by the Finnish population, the Finnish health care infrastructure and large national sample collections. This improved knowledge should provide us with new tools to develop more individualized health care. The recent development of high throughput genotyping and sequencing techniques has made this a realistic goal. The unique setting provided by the Finnish infrastructure has stimulated several Group Members: large whole exome and whole genome sequencing projects, which have organized PI: Aarno Palotie themselves in a collaborative initiative called SISu (Sequencing Initiative Suomi). Senior Researcher: Maija Wessman This collaboration includes researchers from FIMM, THL, Lund University, the Broad PhD Students: Tiia Luukkonen, Mikko Muona, Institute of MIT and Harvard, Michigan University, UCLA, NIH, Oxford University and Olli Pietiläinen the Wellcome Trust Sanger Institute. During 2012, the SISu project has produced the Technicians: Eija Hämäläinen, Elli Kempas (until August complete genome or exome (coding areas of the genome) sequence of thousands of 2012) Finns. When this is combined with the existing genome-wide genotyping (GWA) data Research Nurses: Carita Jussila, Leena Leikas, from more than 50,000 Finns, we have a rich resource that can be further expanded Anne Nyrhinen and used to facilitate a more comprehensive understanding of the genome landscape Project Coordinator: Sari Kivikko associated with diseases that are major health burdens to the population. Our group has a special interest in the genetics of neurological and neuro- Collaborators in the Helsinki University Central developmental traits. Also much of this work draws on the unique clinical and Hospital: Ville Artto, Markus Färkkilä, Mikko Kallela, Salli Vepsäläinen population-based samples collected from the Finnish founder population. These include such clinical collections as the Finnish Migraine Family sample (collected by Dr. Mikko Kallela), the Finnish Schizophrenia family samples (collected by Dr. Jouko Lönnqvist) and the Finnish Autism Sample collection (collected by Dr. Lennart von Wendt) and such population cohorts as the Finrisk, Helsinki Birth Cohort, Northern Finnish Birth Cohort and Health 2000 cohorts (www.nationalbiobanks.fi). To combine different fields of expertise and to have sufficient power, these studies are performed in collaboration with several international groups and high throughput platforms. The wealth of multiple large study samples enables the group to use different study designs for genome variant identification and verification and for the estimation of the size of the effect contributed by the variants. These studies include the UK10K study (www.UK10K.org) and GWAs studies of the International Headache Genetics Consortium chaired by Dr. Palotie Dr. Palotie is a faculty member at the Wellcome Trust Sanger Institute in Cambridge UK and a visiting faculty member at the Broad Institute of MIT and Harvard.

Key publications: Freilinger T, Anttila V, de Vries B, Malik R, Kallela M, Terwindt GM, Pozo-Rosich P, Winsvold B, Nyholt DR, van Oosterhout WP, Artto V, Todt U, Hämäläinen E, Fernández-Morales J, Louter MA, Kaunisto MA, Schoenen J, Raitakari O, Lehtimäki T, Vila-Pueyo M, Göbel H, Wichmann E, Sintas C, Uitterlinden AG, Hofman A, Rivadeneira F, Heinze A, Tronvik E, van Duijn CM, Kaprio J, Cormand B, Wessman M, Frants RR, Meitinger T, Müller-Myhsok B, Zwart JA, Färkkilä M, Macaya A, Ferrari MD, Kubisch C, Palotie A, Dichgans M, van den Maagdenberg AM: International Headache Genetics Consortium. Genome-wide association analysis identifies susceptibility loci for migraine without aura. Nat Genet. 2012 Jun 10;44(7):777-82. Gaál EI, Salo P, Kristiansson K, Rehnström K, Kettunen J, Sarin AP, Niemelä M, Jula A, Raitakari OT, Lehtimäki T, Eriksson JG, Widen E, Günel M, Kurki M, von Und Zu Fraunberg M, Jääskeläinen JE, Hernesniemi J, Järvelin MR, Pouta A; The International Consortium for Blood Pressure Genome- Wide Association Studies (ICBP-GWAS), Newton-Cheh C, Salomaa V, Palotie A, Perola M: Intracranial Aneurysm Risk Locus 5q23.2 Is Associated with Elevated Systolic Blood Pressure. PLoS Genet. 2012 Mar;8(3):e1002563.

FIMM • 19 Inouye M, Ripatti S, Kettunen J, Lyytikäinen LP, Oksala N, Laurila PP, Kangas AJ, Soininen P, Savolainen MJ, Viikari J, Kähönen M, Perola M, Salomaa V, Raitakari O, Lehtimäki T, Taskinen MR, Järvelin MR, Ala-Korpela M, Palotie A, de Bakker PI: Novel Loci for metabolic networks and multi- tissue expression studies reveal genes for atherosclerosis. PLoS Genet. 2012 Aug;8(8):e1002907 Kettunen J, Tukiainen T, Sarin A-P, Ortega-Alonso A, Tikkanen E, Lyytikäinen L-P, Kangas AJ, Soininen P, Würtz P, Silander K, Dick DM, Rose RJ, Savolainen MJ, Viikari J, Kähönen M, Lehtimäki T, Pietiläinen KH, Inouye M, McCarthy MI, Jula A, Eriksson J, Raitakari OT, Salomaa V, Kaprio J, Järvelin M-R, Peltonen L, Perola M, Freimer NB, Ala-Korpela M, Palotie A, Ripatti S: Genome-wide association study identifies multiple loci influencing human serum metabolite levels. Nature Genetics, Jan 29;44(3):269-76, 2012. External research funding: Academy of Finland and Finland Distinguished Professor programme, host for Professor Leif Groop, Helsinki Biomedical Graduate Program (HBGP), Sohlberg Foundation, Sigrid Jusélius Foundation, EU-FP7: SYNSYS, NIH/RFA-HL-12-007, Genomic and Metabolomic Profiling of Finnish Familial Dyslipidemia Families

20 • FIMM Group Hennah Psychiatric genetics: genes, networks and translation

Academy Research Fellow William Hennah, PhD

sychiatric illnesses are debilitating disorders that damage functions in the entire Prange of human mental activity. Our group aims to further the understanding of these disorders through the analysis of the genetic mechanisms that undoubtedly underlie them. The group was founded at FIMM in 2012 with the intention to use next generation sequencing to identify novel functional variations, from within Group Members: genomic regions with prior evidence for involvement in schizophrenia in the Finnish PI: William Hennah population. Building upon our prior studies, this sequencing approach will start with Postdoctoral Researchers: Alfredo Ortega-Alonso, the DISC1 locus. Where, within Finnish cohorts, we have previously observed linkage Liisa Tomppo and association to schizophrenia, association of a similar haplotypic background to both bipolar disorder and Asperger syndrome. We therefore intend to specifically demonstrate a shared genetic etiology underlying distinct clinical phenotypes. If such a hypothesis can be demonstrated, it paves the way for variants to be used in aiding diagnoses of such disorders. Specifically, given the range of mental illness phenotypes being associated with DISC1, it is possible to suggest that genetics may soon underpin how we group and treat these phenotypes. Since any functional variants identified will increase risk to, but not cause, a psychiatric diagnosis, we will study any variants beyond their initial observation. Initially, we plan to use any variants identified within the existing genome-wide data, with the intention it will aid the identification of new loci for future sequencing. Such an approach can be continually fed back on itself, allowing for multiple regions and variants to be identified, many of which will overlap in some families, providing a novel insight into how networks of genes combine to increase risk to mental illness. Further, we plan to study identified functional variants with regard to potentially underlying alternative traits. This would enable us to translate these findings, improving our understanding of how the brain works. In the schizophrenia family cohort, we have neuropsychological, biological and treatment related measures, which are used to start the unravelling of the true function of these genetic variants. Since this data already exists, the identification of any functional variants can go from end-state diagnosis to alternative traits, to biological measures and to treatment implication in a single sample, greatly accelerating the translational aspect of our research.

Key publications: Tomppo T, Ekelund J, Lichtermann D, Veijola J, Järvelin MR, Hennah W. DISC1 conditioned GWAS for psychosis proneness in a large Finnish birth cohort. PLoS One. 2012; 7(2): e30643. Hennah W, Thomson P, McQuillin A, Bass N, Loukola A, Anjorin A, Blackwood D, Curtis D, Deary IJ, Harris SE, Isometsä ET, Lawrence J, Lönnqvist J, Muir W, Palotie A, Partonen T, Paunio T, Pylkkö E, Robinson M, Soronen P, Suominen K, Suvisaari J, Thirumalai S, St Clair D, Gurling H, Peltonen L, Porteous D. DISC1 association, heterogeneity and interplay in schizophrenia and bipolar disorder. Mol Psychiatry. 2009;14(9):865-73. Hennah W and Porteous D. The DISC1 pathway modulates expression of neurodevelopmental, synaptogenic and sensory perception genes. PLoS One. 2009; 4(3):e4906. Hennah W, Tomppo L, Hiekkalinna T, et al. Families with the risk allele of DISC1 reveal a link between schizophrenia and another component of the same molecular pathway, NDE1. Hum Mol Genet. 2007 1;16(5):453-62. External research funding: Academy of Finland

FIMM • 21 Group Palmgren Data integration and statistical modelling

FiDiPro Professor Juni Palmgren, PhD (Finland Distinguished Professor, Academy of Finland)

he Palmgren group has a strong biostatistics background coupled with efforts Tto integrate data and the modelling process. Some of the on-going projects are collaborations between Karolinska Institutet, where Palmgren has her Swedish base, and the FIMM human genomics groups. Focus during 2012 has been on: Gene - environment interplay regulating human metabolism: Alfredo Ortega-Alonso Group Members: has focused on developing complex modelling strategies to study gene – environment PI: Juni Palmgren interplay regulating human metabolism. Heritability estimates for ~140 metabolic Postdoctoral Researchers: Alfredo Ortega-Alonso, traits utilizing data from the FinnTwin12, FinnTwin16 and Northern Finland Birth Ola Spjuth Cohort 1966 studies revealed that previous Finnish heritability estimates may have been confounded by the genetic relatedness of the samples utilized. Classical biometric modelling, limiting pathway modelling, variance components models and restricted maximum likelihood tests were used. The role of sex in the genetic regulation of metabolism: Genomic analyses investigated the role of sex in the genetic regulation of metabolism. Genome-wide association analyses in “the Northern Finland Birth Cohort 1966” and “the Cardiovascular Risk in Young Finns Study” revealed 20 genetic loci showing potential sex-heterogeneity effects on the regulation of different serum metabolites, in addition to more than 100 loci showing sex-specific genetic effects. Replication in other European populations is needed. Sample availability platform: Collaborative work was pursued on the KITE platform (successor to SAIL) for Sample Availability between FIMM (lead by Timo Miettinen) with contributions from Karolinska Institutet (lead by Ola Spjuth). Karolinska contributions were primarily in user interface development, data, and use cases for integration of data between biobanks and health registries in prostate, breast, and cervix cancer. Results on HPV16 Viral Load and Risk of In Situ and Invasive Squamous Cervical Cancer have been obtained. Development continues in 2013. Integrated data-infrastructure for population biobanks and registries: The on-going revision of the EU Data Directive for personal data has during 2012 proceeded to the Nordic level. As members of the steering group for the NordForsk Noria-net Registers Palmgren (and Marjut Salokannel) have contributed to the workshop program “Responsible Nordic Data Sharing” organized by the Nordic Council of Ministers in Stockholm March 5, 2013.

Key publications: Krestyaninova M, Spjuth O, Hastings J, Dietrich J, Rebholz-Schuhmann D. Biobank Metaportal to Enhance Collaborative Research: sail.simbioms.org Journal of Systemics, Cybernetics and Informatics. 2012 (vol 10, N 4), pp 5-10. Sundstrom K, Ploner A, Dahlstrom LA, Palmgren J, Dillner J, Adami HO, Ylitalo N, Sparen P. Prospective Study of HPV16 Viral Load and Risk of In Situ and Invasive Squamous Cervical Cancer. Cancer epidemiology, biomarkers & prevention: a publication of the American Association for Cancer Research, co-sponsored by the American Society of Preventive Oncology. 2013 Jan;22(1):150-8. Poster presentations O. Spjuth, J. Dietrich, J. Hastings, J. Palmgren, JE Litton, and M. Krestyaninova. The SAIL platform: Enhancing biobank-based collaborative studies, HandsOn:BioBanks 2012, Uppsala, Sweden External research funding: Academy of Finland, Biocenter Finland, Swedish Research Council, Swedish eScience Center, SeRC

22 • FIMM Group Ripatti Statistical and computational genetics

Professor, FIMM-EMBL Group Leader (supported by Sigrid Jusélius Foundation) Samuli Ripatti, PhD

ur research focuses on studying genetic variation and its relation to risks of Ocommon complex diseases and risk factors. In particular, we have studied genetics of cardiovascular diseases, circulating lipids and serum metabolites and developed approaches to analyse systems data across multiple high-throughput technologies. We also evaluate how the emerging genetic information can be turned into tools for disease risk evaluation and risk stratification. Our research often calls for novel approaches to Group members: computational and statistical methodology and uses genetically exceptionally well- PI: Samuli Ripatti characterized Finnish population-based cohorts with rich phenotypic data. During the past year, we first, catalogued genetic variants modifying serum Postdoctoral Researchers: Johannes Kettunen, metabolite levels, second, studied the role of metabolite networks on atherosclerosis, Matti Pirinen, Taru Tukiainen, Peter Würtz third, described the role of inflammation in low HDL-C patients using a combination of PhD and MD Students: Himanshu Chheda genomic, transcriptomic and lipidomic profiling, and fourth, fine-mapped known lipid (co-supervised with Tero Aittokallio), modifying loci using rich lipoprotein sub-class data. In addition, we participated in several Pirkka-Pekka Laurila, Pietari Ripatti, Antti-Pekka Sarin, Ida Surakka, Emmi Tikkanen, Mari Rossi large-scale efforts presenting tens of novel loci for cardio metabolic diseases and traits. (co-supervised with Iiris Hovatta) As of February 2013 Group Leader Ripatti is Professor of Biometry at Faculty of Medicine, University of Helsinki and Honorary Faculty Member at Wellcome Trust Project Coordinator: Huei-yi Shen Sanger Institute.

Recent Key Publications: Kettunen J, Tukiainen T, Sarin A-P, Ortega-Alonso A, Tikkanen E, Lyytikäinen L-P, Kangas AJ, Soininen P, Würtz P, Silander K, Dick DM, Rose RJ, Savolainen MJ, Viikari J, Kähönen M, Lehtimäki T, Pietiläinen KH, Inouye M, McCarthy MI, Jula A, Eriksson J, Raitakari OT, Salomaa V, Kaprio J, Järvelin M-R, Peltonen L, Perola M, Freimer NB, Ala-Korpela M, Palotie A, Ripatti S: Genome-wide association study identifies multiple loci influencing human serum metabolite levels. Nature Genetics, Jan 29;44(3):269-76, 2012. Inouye M, Ripatti S, Kettunen J, Lyytikäinen LP, Oksala N, Laurila PP, Kangas AJ, Soininen P, Savolainen MJ, Viikari J, Kähönen M, Perola M, Salomaa V, Raitakari O, Lehtimäki T, Taskinen MR, Järvelin MR, Ala-Korpela M, Palotie A, de Bakker PI: Novel Loci for metabolic networks and multi- tissue expression studies reveal genes for atherosclerosis. PLoS Genet. 2012 Aug;8(8):e1002907 Tukiainen T, Kettunen J, Kangas AJ, Lyytikäinen LP, Soininen P, Sarin AP, Tikkanen E, O’Reilly PF, Savolainen MJ, Kaski K, Pouta A, Jula A, Lehtimäki T,Kähönen M, Viikari J, Taskinen MR, Jauhiainen M, Eriksson JG, Raitakari O, Salomaa V, Järvelin MR, Perola M, Palotie A, Ala-Korpela M, Ripatti S. Detailed metabolic and genetic characterization reveals new associations for 30 known lipid loci. Hum Mol Genet. 2012 Mar 15;21(6):1444-55. Laurila PP, Surakka I, Sarin AP, Yetukuri L, Hyötyläinen T, Söderlund S, Naukkarinen J, Tang J, Kettunen J, Mirel DB, Soronen J, Lehtimäki T, Ruokonen A, Ehnholm C, Eriksson JG, Salomaa V, Jula A, Raitakari OT, Järvelin MR, Palotie A, Peltonen L, Oresic M, Jauhiainen M, Taskinen MR, Ripatti S. Genomic, Transcriptomic, and Lipidomic Profiling Highlights the Role of Inflammation in Individuals With Low High-density Lipoprotein Cholesterol. Arterioscler Thromb Vasc Biol. 2013 Feb 14. [Epub ahead of print] PubMed PMID: 23413431. CARDIoGRAMplusC4D Consortium. Large-scale association analysis identifies new risk loci for coronary artery disease, Nat Genet. 2013 Jan;45(1):25-33 Kristiansson K, Perola M, Tikkanen E, Kettunen J, Surakka I, Havulinna AS, Stancáková A, Barnes C, Widen E, Kajantie E, Eriksson JG, Viikari J, Kähönen M, Lehtimäki T, Raitakari OT, Hartikainen AL, Ruokonen A, Pouta A, Jula A, Kangas AJ, Soininen P, Ala-Korpela M, Männistö S, Jousilahti P, Bonnycastle LL, Järvelin MR, Kuusisto J, Collins FS, Laakso M, Hurles ME, Palotie A, Peltonen L, Ripatti S, Salomaa V. Genome-wide screen for metabolic syndrome susceptibility Loci reveals strong lipid gene contribution but no evidence for common genetic basis for clustering of metabolic syndrome traits. Circ Cardiovasc Genet. 2012 Apr 1;5(2):242-9. Palotie A, Widén E, Ripatti S. From genetic discovery to future personalised health research. N Biotechnol. 2012 Nov 16 External research funding: Academy of Finland, Helsinki Graduate Program in Biotechnology and Molecular Biology (GPBM), Helsinki Biomedical Graduate Program (HBGP), Finnish Foundation for Cardiovascular Research, EU-FP7: ENGAGE and BioSHare

FIMM • 23 Group Saarela Genetics of Autoimmune Diseases

Research Director Janna Saarela, MD, PhD

he human immune system is a complex and sophisticated system, which has a Tsimple, yet very important mission: to seek and kill attackers. While defective immune system, severe combined immunodeficiency and a lack of immune system cells cause life-threatening diseases, other immune disorders result from either an excessive immune response or an “autoimmune attack”. The same genes are frequently associated with multiple autoimmune diseases and some of them are also known to cause immune deficiencies. Our goal is to improve understanding of biological pathways and pathogenic mechanisms behind common and rare immune diseases, especially multiple sclerosis (MS) and primary immune deficiencies (PIDD). To further the understanding of MS through the analysis of the genetic mechanisms that underlie the disease, we aim to identify novel predisposing genes and functional variants within the identified regions by genome-wide analyses of large international cohorts, and by targeted resequencing of the unique familial samples, originating from a high-risk MS subisolate of Southern Ostrobothnia with increased prevalence and familial occurrence of the disease. The impact of the identified genetic variants will be further characterized in the Finnish population cohorts. In 2012, we initiated a novel research programme with clinical experts of the Helsinki University Central Hospital (HUCH) treating PIDD patients, Drs Mikko Group Members: Seppänen, Kaarina Heiskanen and Paula Klemetti from adult and pediatric immune deficiency units of HUCH being the main collaborators. The research programme PI: Janna Saarela aims to (1) identify disease causing mutations in severe primary immune deficiency Postdoctoral Researcher: Annu Näkki families, (2) evaluate the usage of novel genomics methods to improve the clinical PhD Students: Virpi Leppä, Anna-Maija Sulonen, diagnostics of PIDD, (3) identify novel immune deficiency syndromes, and (4) Luca Trotta, Henrikki Almusa, Meri Kaustio functionally characterize selected novel mutations identified by sequencing to further (rotation Dec-Feb) elucidate the molecular mechanism of the disease. Availability of the sequence level data from large Finnish population cohorts will allow us to expand the research focus to include also milder and more targeted immune deficiencies enriched in the Finnish population.

Key Publications: International Multiple Sclerosis Genetics Consortium & Wellcome Trust Case Control Consortium 2, Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis. Nature. 2011 476:214-9. Sulonen AM, Ellonen P, Almusa H, Lepistö M, Eldfors S, Hannula S, Miettinen T, Tyynismaa H, Salo P, Heckman C, Joensuu H, Raivio T, Suomalainen A, Saarela J. Comparison of solution-based exome capture methods for next generation sequencing. Genome Biol. 2011 Sep 28;12(9):R94. Kemppinen AK, Kaprio J, Palotie A, Saarela J. Systematic review of genome-wide expression studies in multiple sclerosis. BMJ Open. 2011, 1:e000053. Jakkula E, Leppä V, Sulonen AM, Varilo T, Kallio S, Kemppinen A, Purcell S, Koivisto K, Tienari P, Sumelahti ML, Elovaara I, Pirttilä T, Reunanen M, Aromaa A, Oturai AB, Søndergaard HB, Harbo HF, Mero IL, Gabriel SB, Mirel DB, Hauser SL, Kappos L, Polman C, De Jager PL, Hafler DA, Daly MJ, Palotie A, Saarela J, Peltonen L. Genome-wide association study in a high-risk isolate for multiple sclerosis reveals associated variants in STAT3 gene. Am J Hum Genet. 2010 Feb 12;86(2):285-91. External research funding: Sigrid Jusélius Foundation, Emil Aaltonen Foundation, the Finnish Medical Foundation. The group is also involved in infrastructure programmes: Biocenter Finland (Genome-wide Methods network), Biomedinfra (ELIXIR, BBMRI and EATRIS collaboration).

24 • FIMM Group Widen Genetics of Puberty and Adult Health

Senior Researcher Elisabeth Widén, MD, PhD

uberty is one of the most important milestones in life. Yet, the molecular Pevents controlling its timely onset are poorly understood. A wealth of previous epidemiological data pinpoints a link between early puberty and adult health outcomes, e.g. obesity and type 2 diabetes. Nonetheless, the mediating mechanisms remain unclear, and the majority of the data are based on studies including females only. The goal of our research is to discover and characterize novel mechanisms influencing pubertal maturation and growth. The strategy is (1) to identify the Group Members: underlying genes by genome-wide association (GWA) utilizing large population PI: Elisabeth Widén cohorts with longitudinal growth data, and (2) to characterize their impact on adult PhD Students: Diana Cousminer, Jaakko Leinonen health in large population-based cohorts. To meet the first aim, our group has lead a large international collaborative GWA meta-analysis project capitalizing extensive longitudinal height data from more than 18,000 study subjects of Finnish and European descent. We identified ten significantly associated loci, including a novel variant highlighting a role for the extracellular signal-regulated kinase 1 (MAPK3), both in the timing of puberty and childhood growth. We also found that the identified pubertal growth loci all impacted on height or BMI across multiple periods of development. These results are in press in Human Molecular Genetics. Addressing our second aim, we analysed a Finnish birth cohort with data on longitudinal childhood growth and a wide spectrum of adult metabolic risk factors. We found that earlier pubertal timing associates with adult metabolic syndrome- related derangements both in males and females. This association was independent of preceding childhood growth events, emphasizing the fact that mechanisms advancing puberty may also directly contribute to adult metabolic disorders. In a separate study, we examined the association of the puberty-associated gene LIN28B on adult body size and metabolic profiles in a population-based cohort of 26,000 Finnish study subjects. The data showed that LIN28B, indeed, has pleiotropic effects, impacting on obesity-related traits in adulthood. Our future research aims at functional characterization of the genes pinpointed by our GWA studies. Unexpectedly, a significant proportion of them are evolutionarily conserved and expressed already during fetal life. We are now characterizing their impact on early embryonic development in zebrafish, a model system allowing efficient evaluation of early development and growth.

Key Publications: Horikoshi M, Yaghootkar H, Mook-Kanamori DO. New loci associated with birth weight identify genetic links between intrauterine growth and adult height and metabolism. Nat Genet. 2013;45:76-82 Leinonen JT, Surakka I, Havulinna AS, Kettunen J, Luoto R, Salomaa V, Widén E. Association of LIN28B with adult adiposity-related traits in females. PLoS One. 2012;7:e48785 Widén E, Silventoinen K, Sovio U, Ripatti S, Cousminer DL, Hartikainen AL, Laitinen J, Pouta A, Kaprio J, Järvelin MR, Peltonen L, Palotie A. Pubertal timing and growth influences cardiometabolic risk factors in adult males and females. Diabetes Care. 2012 Apr;35(4):850-6. Elks CE, Perry JR, Sulem P, et al. Thirty new loci for age at menarche identified by a meta-analysis of genome-wide association studies. Nat Genet. 2010;42:1077-1085 Widén E, Ripatti S, Cousminer DL, Surakka I, Lappalainen T, Järvelin MR,Eriksson JG, Raitakari O, Salomaa V, Sovio U, Hartikainen AL, Pouta A, McCarthy MI, Osmond C, Kajantie E, Lehtimäki T, Viikari J, Kähönen M, Tyler-Smith C,Freimer N, Hirschhorn JN, Peltonen L, Palotie A. Distinct variants at LIN28B influence growth in height from birth to adulthood. Am J Hum Genet. 2010 May 14;86(5):773-82. External research funding: Academy of Finland, Finska Läkaresällskapet, Helsinki Biomedical Graduate Program (HBGP)

FIMM • 25 Research Groups in Systems Medicine and Translational Research

Group Kallioniemi Individualized Systems Medicine

Professor Olli Kallioniemi, MD, PhD

aking cancer care more effective and individualized is a central aim for cancer Mresearchers worldwide. This is usually being pursued via DNA sequencing based efforts and the identification of oncogenic driver mutations. We believe and have emerging evidence that this will miss many therapeutic opportunities. In contrast, individualized systems medicine (ISM) may help to uncover targeted drugs and drug combinations with unexpected cancer-specific therapeutic potential. Our new individualized systems medicine study is as part of a “grand challenge” Group Members: programme at FIMM to improve cancer therapy. Using adult Acute Myeloid Leukaemia (AML) as a model disease, we aim to: (1) identify effective targeted drugs PI: Olli Kallioniemi for AML patients by ex-vivo DSRT as well as genomic and molecular profiling, (2) Assistant to Prof. Kallioniemi: Susanna Rosas understand how the molecular and functional features change during drug response Senior Researchers and Visiting Researchers: and resistance based on paired samples, (3) create individual systems medicine Taija af Hällström (also affiliated with Biobank), models of AML driver signals and drug response/resistance, (4) translate these data Vilja Pietiäinen, Päivi Östling (both also affiliated with towards individualized cancer treatment. The personalised medicine collaboration High Throughput Biomedicine Unit), Maija Wolf involves Wennerberg, Heckman/Knowles, Aittokallio and Lundin groups at FIMM and (on personal leave) and Akira Hirasawa clinical collaborators at HUS. Postdoctoral Researchers: Henrik Edgren, In addition, the group is developing similar strategies in prostate cancer, where Sara Kangaspeska, Astrid Murumägi and Teijo Pellinen we work with established cancer cell lines, drug-resistant model systems, patient ex- PhD and MSc Students: Anna Aakula, Sami Blom, vivo material and tumor tissues to profile drug response and resistance. We would Oscar Brück, Poojitha Kota Venkata, Disha Malani, like to identify the genes and signalling pathways that play a key role and could act as John Patrick Mpindi, Kalle Ojala, Khalid Saeed, Dmitrii Bychkov, Susanne Hultsch, Petra Mäki-Teeri predictive biomarkers of drug response and resistance. and Sanna Timonen Senior Laboratory Technicians: Mariliina Arjama, Recent Key Publications: Katja Välimäki (on personal leave) Koskela HLM, Eldfors S, Ellonen P, van Adrichem AJ, Kuusanmäki H, Andersson EI, Lagström S, ClementeMJ, Olson T, Jalkanen SE, Majumder MM, Almusa H, Edgren H, Lepistö M, Mattila P, Guinta Laboratory Technician: Jenni Säilä K, Koistinen P, Kuittinen T, Penttinen K, Parsons A, Knowles J, Saarela J, Wennerberg K, Kallioniemi O, Porkka K, Loughran TP, Heckman C, Maciejewski JP, Mustjoki S. Somatic STAT3 Mutations in Large Granular Lymphocyte Leukemia. NEJM, 2012 May 17;366(20):1905-13 Hanash SM, Baik CS, Kallioniemi O. Emerging molecular biomarkers--blood-based strategies to detect and monitor cancer. Nat Rev Clin Oncol. 2011 Mar;8(3):142-50. Edgren H, Murumagi A, Kangaspeska S, Nicorici D, Hongisto V, Kleivi K, Rye IH, Nyberg S, Wolf M, Borresen-Dale AL, Kallioniemi O. Identification of fusion genes in breast cancer by paired-end RNA- sequencing. Genome Biol. 2011;12(1):R6. Epub 2011 Jan 19. Östling P, Leivonen SK, Aakula A, Kohonen P, Mäkelä R, Hagman Z, Edsjö A, Kangaspeska S, Edgren H, Nicorici D, Bjartell A, Ceder Y, Perälä M, Kallioniemi O. Systematic analysis of microRNAs targeting the androgen receptor in prostate cancer cells. Cancer Res. 2011 Mar 1;71(5):1956-67. External research funding: Academy of Finland, Cancer Society of Finland, Sigrid Jusélius Foundation, Helsinki Biomedical Graduate Program (HBGP), EU-FP7: SYSMIC, PRO-NEST, IMI- PREDECT

26 • FIMM Group Aittokallio Computational Systems Medicine

FIMM-EMBL Group Leader (supported by the University of Helsinki) Tero Aittokallio, PhD, Adjunct Professor

prime challenge in the development of personalised health care strategies is A how to utilize genotypic information when predicting clinical phenotypes of individuals, such as their susceptibility to diseases or response to treatments. One reason why the disease risk and treatment responses have proven so difficult to predict is due to genetic interactions: genetic alterations or other perturbations that have no discernible individual effect on phenotypes may have strong synergistic effects leading either to disease progression, treatment efficacy or toxicity when combined. While such gene-gene interactions are important in many disease phenotypes, Group members: such as in the development of atherosclerosis and treatment of cancers, they have PI: Tero Aittokallio remained difficult to identify on a global scale because of the vast number of possible Senior Researcher: Jing Tang interaction partners and complex genotype-phenotype relationships. Postdoctoral Researchers: Petteri Hintsanen, During 2012, the group developed improved network polypharmacology ap- Antonio Neme proaches, which can provide system-level insights into how cancer survival pathways PhD Students: Bhagwan Yadav, Agnieszka Szwajda can be targeted by synergistic and synthetic lethal interactions through multi–target (co-supervised with Krister Wennerberg), perturbations, as well as applied this in silico approach to selecting the most promis- Himanshu Chheda (co-supervised with Samuli Ripatti). ing drug combinations for experimental evaluation either in vitro or in vivo. In collab- Rotation student: Alok Jaiswal (Dec 2012 - Feb 2013) oration with the Wennerberg, Kallioniemi, and Heckman/Knowles groups at FIMM and clinical collaborators at HUS, we also developed a computational framework for Research Assistants: Tao Xu, Teemu Daniel Laajala quantitative scoring of treatment responses, which enables investigation of cellular addictions and other druggable vulnerabilities in individual cancer samples, as well as systematic stratification of cancer patients and disease subtypes based on their drug sensitivity and resistance profiles. Our future plan is to combine the functional information from high-throughput drug and RNAi screening with complementary information from genomic profiling to provide a more comprehensive network-view of molecular mechanisms behind disease processes and to predict system-level phenotypic responses to genetic and chemical perturbations. Such pharmacogenomic approaches have the potential to identify safe and effective treatment strategies for individual patients. A particular focus will be on predicting synthetic lethal partners of cancer-driving mutations, the optimal targeting of which holds great promise of being a highly specific and selective means to kill the cancer cells without severe side-effects to normal cells.

Key publications: Tang J, Aittokallio T. Network pharmacology strategies toward multi-target anticancer therapies: from computational models to experimental design principles. Current Pharmaceutical Design, Re- view article in Systems and Network Biology in Pharmaceutical Drug Discovery (in press). Laajala TD, Corander J, Saarinen NM, Mäkelä K, Savolainen S, Suominen MI, Alhoniemi E, Mäkelä SI, Poutanen M, Aittokallio T. Improved statistical modeling of tumor growth and treatment effect in pre-clinical animal studies with highly heterogeneous responses in vivo. Clinical Cancer Research 2012; 18: 4385-4396. Okser S, Lehtimäki T, Elo LL, Mononen N, Peltonen N, Kähönen M, Juonala M, Fan YM, Hernesniemi JA, Laitinen T, Lyytikäinen LP, Rontu R, Eklund C, Hutri-Kähönen N, Taittonen L, Hurme M,Viikari JS, Raitakari OT, Aittokallio T. Genetic variants and their interactions in the prediction of increased pre-clinical carotid atherosclerosis - the cardiovascular risk in young Finns study. PLoS Genetics 2010 6(9) e1001146. External research funding: Academy of Finland, Biocenter Finland, Finnish Funding Agency for Technology and Innovation (Tekes), and Helsinki Biomedical Graduate Program (HBGP).

FIMM • 27 Group Kainov Medical Systems Virology

FIMM-EMBL Group Leader (supported by Jane and Aatos Erkko Foundation) Denis Kainov, PhD, Adjunct Professor

iruses cause significant morbidity and mortality. Different prevention and Vtreatment options (e.g. vaccinations and virus-directed drugs) have been developed. However, these as such are insufficient in the face of recent epidemics and pandemics. Our mission is to improve human health using a new concept of controlling viral infections. This concept includes individual assessment and subsequent vaccination of the individuals at risk of developing severe viral infections. This would reduce a number of hospitalizations and healthcare costs, providing Group members: timely and efficient treatment for susceptible individuals. In addition, the concept PI: Denis Kainov includes development of broad-spectrum antivirals for treatment of emerging viral Postdoctoral Researchers: Laura Kakkola, infections. These types of drugs could in the future reinforce the therapeutic arsenal Johanna Lampe and address the needs of the society to control virus outbreaks. PhD Students: Oxana Denisova, Maria Anastasina Our research focuses mainly on influenza A and other respiratory viruses. Our Technician: Minttu Kaloinen, BSc. specific aims are to develop new diagnostic tools and treatment modalities for severe viral infections. During 2012, we improved our method of the whole genome sequencing of respiratory virus isolates from Finnish patients aiming to increase the resolution and accuracy of virus surveillance and outbreak investigations. In addition, we identified three novel host-targeted compounds with broad-spectrum antiviral activity. These drugs create a barrier to viral drug resistance by targeting cellular factors that are essential for virus replication. Our future focus from 2013 inwards is to identify novel viral and host factors that would explain the severity of influenza A virus infection in humans by using population and hospital-based data and samples, large scale viral and host sequencing and genotyping, metabolomics and various chemical and molecular biology tools. This systems virology approach will allow us to develop new diagnostic methods and treatment modalities for severe influenza A and possibly other viral infections.

Key Publications: Smura T, Kakkola L, Blomqvist S, Klemola P, Parsons A, Kallio-Kokko H, Savolainen-Kopra C, Kainov D, Roivainen M. Molecular evolution and epidemiology of echovirus 6 in Finland. Infect Genet Evol. 2013 Feb 24;16C:234-247. Denisova OV, Kakkola L, Feng L, Stenman J, Nagaraj A, Lampe J, Yadav B, Aittokallio T, Kaukinen P, Ahola T, Kuivanen S, Vapalahti O, Kantele A, Tynell J, Julkunen I, Kallio-Kokko H, Paavilainen H, Hukkanen V, Elliott RM, De Brabander JK, Saelens X, and Kainov DE. Obatoclax, saliphenylhalamide and gemcitabine inhibitit influenza A virus infection. J Biol Chem. 2012; 287: 35324-32. Feng L, Lintula S, Ho TH, Anastasina M, Paju A, Haglund C, Stenman UH, Hotakainen K, Orpana A, Kainov D, Stenman J. (2012) Technique for strand-specific gene-expression analysis and monitoring of primer- independent cDNA synthesis in reverse transcription. BioTechniques. 52: 263-270. Mueller KH, Kakkola L, Nagaraj AS, Cheltsov AV, Anastasina M, Kainov DE. (2012) Emerging cellular targets for influenza antiviral agents. Trends Pharmacol Sci. 33: 89-99 External research funding: Academy of Finland, CIMO, Helsinki Biomedical Graduate Program (HBGP)

28 • FIMM Group Knowles Personalised Cancer Medicine

FIdiPro Professor Jonathan Knowles, PhD (Finland Distinguished Professor, Tekes)

mproved genomic and next generation sequencing technologies have yielded an Ienormous amount of information and provided numerous insights into disease pathogenesis. For cancer, these tools have been particularly useful for identifying new biomarkers and therapeutic targets. However, translating these findings into patient care remains a major challenge. The primary focus of our group is leukaemia with a particular emphasis on understanding disease development and drug resistance mechanisms, but at the same time, translating our discoveries into immediate implementation for patient treatment. We use next generation exome, whole genome and transcriptome sequencing, plus proteomic analyses of patient samples collected at diagnosis and relapse. Analyses of serial samples from the same patient allow us to identify initiating events in the patient’s disease, as well as important driving and resistance mechanisms. We follow-up with functional validation studies combined with high- throughput screening to identify drugs that can target chemorefractory cells. In collaboration with the Hematology Research Unit Helsinki, we identified the STAT3 gene to be recurrently mutated in large granular lymphocytic leukaemia, which is the first genomic alteration associated with this disease. Our studies of chemorefractory leukaemia patient samples have highlighted the disease heterogeneity and identified drug resistant sub-clones, and in collaboration with other groups at FIMM and Helsinki University Central Hospital, have been able to Group Members: translate findings from high throughput drug screens into patient treatments. At the PI: Jonathan Knowles same time, we have been working towards improved methodologies for sustained ex vivo culture of patient tumour cells, which can be used as personalised disease models Co-PI: Caroline Heckman and applied to a variety of platforms for individualized assay results. Assistant to Prof. Knowles: Susanna Rosas Senior Research Technician: Alun Parsons Key Publications: Bioinformatician: Samuli Eldfors Koskela HL, Eldfors S, Ellonen P, van Adrichem AJ, Kuusanmäki H, Andersson EI, Lagström S, PhD Students: Riikka Karjalainen, Jarno Kivioja, Ashwini Clemente MJ, Olson T, Jalkanen SE, Majumder MM, Almusa H, Edgren H, Lepistö M, Mattila P, Guinta Kumar, Heikki Kuusanmäki, K, Koistinen P, Kuittinen T, Penttinen K, Parsons A, Knowles J, Saarela J, Wennerberg K, Kallioniemi O, Muntasir Mamun Majumder Porkka K, Loughran TP Jr, Heckman CA, Maciejewski JP, Mustjoki S. Somatic STAT3 mutations in large (co-supervised with Krister Wennerberg) granular lymphocytic leukemia. N Engl J Med. 2012 17;366(20):1905-13. Jalkanen SE, Lahesmaa-Korpinen AMK, Heckman C, Rantanen V, Porkka K, Hautaniemi S, Mustjoki S. Phosphoprotein profiling predicts response to tyrosine kinase inhibitor therapy in chronic myeloid leukemia patients. Experimental Hematology. 2012; 40: 704-714. Heckman CA, Kontro M, Pemovska T, et al. High-throughput ex vivo drug sensitivity and resistance testing (DSRT) integrated with deep genomic and molecular profiling reveal new therapy options with targeted drugs in subgroups of relapsed chemorefractory AML. Blood. 2012; 120: 288 (abstract). External research funding: Tekes FiDiPro

FIMM • 29 Group Kuznetsov Breast Cancer Biology

FIMM-EMBL Group Leader (supported by Finnish Medical Foundation and Sigrid Jusélius Foundation) Academy Research Fellow Sergey Kuznetsov, PhD

reast cancer is the most common malignancy in women affecting almost every Bthird woman in developed countries. Somatic and germ line mutations in essential tumour suppressors and oncogenes play a crucial role in development of every cancer. However, in spite of recent advances in DNA sequencing technologies, genotypic Group Members: information finds a very limited use in today’s clinical oncology practice. Our group aims to enable a wider use of genotypic information for personalised PI: Sergey Kuznetsov treatment of breast cancer. First, we try to identify new essential breast cancer Postdoctoral Researcher: Pauliina Munne genes. Second, we model particular mutations in vitro and/or in vivo to understand PhD Students: Manuela Tumiati, Yuexi Gu, how they function in the breast under different conditions. And third, we use these Daria Bulanova models to identify therapeutic strategies that could potentially be applied to breast Master Student: Sharif Iqbal cancer patients with these mutations. Technicians: Sonja Koopal, Sanna Uusivirta In 2012, in a close collaboration with Dr. Evgeny Imyanitov, Russia, and FIMM Sequencing Unit, we sequenced several patients with bilateral breast cancer and identified two new genes likely playing a role in breast cancer predisposition (Kuligina et al., 2013). One of them is currently being pursued as a potential modifier of breast cancer risk in BRCA1 mutation carriers (Bulanova et al., in preparation). We also used mice and primary mouse cells mutated for the major tumour suppressor p53 to get insight into its role in morphogenetic processes. Our findings suggest new ways to treat p53-mutated cancers (Munne et al., in preparation). In addition, we continued working on DNA repair genes known to predispose to breast cancer such as BRCA1 and RAD51C. We generated a new highly reliable mouse model of Rad51c-mediated carcinogenesis. Here, mutant mice invariably develop tumours in several glands around six months of age and may become a valuable preclinical model of RAD51C-related cancers (Tumiati et al., in preparation). In collaboration with the FIMM RNAi Unit and Dr. Heli Nevanlinna, HUS, we also carried out a functional screen for genes modifying the effect of ionizing radiation onBRCA1-deficient cells (Gu et al., in preparation). These studies pave the way to a better use of cancer-specific mutations in selecting therapeutic strategies for individual cancer patients.

Key Publications: Kuligina ESh, Sokolenko AP, Mitiushkina NV, Abysheva SN, Preobrazhenskaya EV, Gorodnova TV, Yanus GA, Togo AV, Cherdyntseva NV, Bekhtereva SA, Dixon JM, Larionov AA, Kuznetsov SG, Imyanitov EN. Value of bilateral breast cancer for identification of rare recessive at-risk alleles: evidence for the role of homozygous GEN1 c.2515_2519delAAGTT mutation. Fam Cancer. 2013, 12(1): 129-32 Sokolenko AP, Iyevleva AG, Preobrazhenskaya EV, Mitiushkina NV, Abysheva SN, Suspitsin EN, Kuligina ESh, Gorodnova TV, Pfeifer W, Togo AV, Turkevich EA, Ivantsov AO, Voskresenskiy DV, Dolmatov GD, Bit-Sava EM, Matsko DE, Semiglazov VF, Fichtner I, Larionov AA, Kuznetsov SG, Antoniou AC, Imyanitov EN. High prevalence and breast cancer predisposing role of the BLM c.1642 C>T (Q548X) mutation in Russia. Int J Cancer. 2012, 130(12): 2867-73. Biswas K, Das R, Alter BP, Kuznetsov SG, Stauffer S, North SL, Burkett S, Brody LC, Meyer S, Byrd RA, Sharan SK. A comprehensive functional characterization of BRCA2 variants associated with Fanconi anemia using mouse ES cell-based assay. Blood. 2011, 118(9): 2430-42 Kuznetsov SG, Haines DC, Martin BK, Sharan SK. Loss of Rad51c leads to embryonic lethality and modulation of Trp53-dependent tumorigenesis in mice. Cancer Res. 2009, 69(3): 863-72 Kuznetsov SG, Liu P, Sharan SK. Mouse embryonic stem cell-based functional assay to evaluate mutations in BRCA2. Nat Med. 2008,14(8): 875-81. External research funding: Academy of Finland, Biocenter Finland, Cancer Society of Finland, Helsinki Biomedical Graduate Program (HBGP), Helsinki Graduate Program in Biotechnology and Molecular Biology (GPBM), and Finnish Cultural Foundation.

30 • FIMM Group Lundin Clinical Informatics and Image-Based Diagnostics

Research Director Johan Lundin, MD, PhD

he group develops methods for personalised prediction of disease outcome and Timage based diagnostics. Genetic and molecular information combined with clinical data by the use of advanced informatics support will help identify patients at risk for disease recurrence and tailor individualized treatment, particularly in cancer. Our goal is to promote implementation of new decision-support technology, as well as improve the flow of information from basic research to the clinic. We have developed an online risk calculator - “Prognomics” - for personalised Group Members: prediction of cancer outcome. The calculator is an extension of our previously PI: Johan Lundin published “case-match” method and is connected to a database with molecular, as well as clinical and outcome data on more than five million cases from fifteen Senior Researcher: Nina Linder countries. Survival estimates can be retrieved for all major cancers and the extensive Postdoctoral Researchers: Anne Grote, Juho Konsti, database allows for estimation of risk even in rare subgroups. The case-match Ville Ojansivu, Margarita Walliander approach is also used for explorative analysis of novel biomarkers and is linked to our PhD Students: Tiina Lehtimäki, Mikael Lundin, image analysis system described below. Antti Suutala, Riku Turkki The other major research area is image-based diagnostics, with special focus on microscopy images. We are exploring high-throughput computer assisted methods for automated analysis of digitized cancer tissue (breast, prostate and colorectal) and microbiological samples (e.g. malaria). The webmicroscopy developed by our research group (fimm.webmicroscope. net) enables the digitization of entire microscope specimens and viewing, as well as processing the virtual slides through web-, mobile- or large-size multitouch interfaces. The technology is implemented as a research infrastructure on a national level within Biocenter Finland and on an international level via the EU funded EATRIS. Applications of the technology include analysis and management of tissue microarrays, laboratory quality assurance, consultation and education. The methods are implemented for remote diagnostics within global health in collaboration with Karolinska Institutet, Stockholm. In 2012, the Prognomics prognostic tool was developed for sarcomas (1) and the case-match method was applied for study of the biomarker XOR (2). An automated computer vision method for segmenting tumour epithelium from stroma (3) and a study regarding the effect of compression and scaling on automated IHC scorings (4) was published.

Photo by Aleksi Poutanen

FIMM • 31 Key Publications: A web-based prognostic tool for extremity and trunk wall soft tissue sarcomas and its external validation. Sampo M, Tarkkanen M, Tukiainen E, Popov P, Gustafson P, Lundin M, Böhling T, Blomqvist C, Lundin J. Br J Cancer. 2012 Mar 13;106(6):1076-82. Decreased xanthine oxidoreductase (XOR) is associated with a worse prognosis in patients with serous ovarian carcinoma.Linder N, Bützow R, Lassus H, Lundin M, Lundin J. Gynecol Oncol. 2012 Feb;124(2):311-8. Identification of tumor epithelium and stroma in tissue microarrays using texture analysis. Linder N, Konsti J, Turkki R, Rahtu E, Lundin M, Nordling S, Ahonen T, Pietikainen M, Lundin J. Diagn Pathol. 2012 Mar 2;7(1):22. Effect of image compression and scaling on automated scoring of immunohistochemical stainings Photo by Rauno Träskelin and segmentation of tumor epithelium. Juho Konsti, Mikael Lundin, Nina Linder, Caj Haglund, Carl Blomqvist, Heli Nevanlinna, Kirsimari Aaltonen, Stig Nordling and Johan Lundin. Diagn Pathol. 2012 Mar 21;7:29. An open source, MATLAB-based annotation tool for virtual slides. Riku Turkki, Margarita Walliander, Ville Ojansivu, Nina Linder, Mikael Lundin, Johan Lundin. Diagn Pathol. 2012, suppl. Automated segmentation of blood cells in Giemsa stained thin smear images. Margarita Walliander, Riku Turkki, Nina Linder, Ville Ojansivu, Juho Konsti, Mikael Lundin, Taru Meri, Ville Holmberg, Johan Lundin. Diagn Pathol. 2012, suppl. Automated classification of breast cancer images according to morphological features using LPQ/LBP texture descriptors and an SVM classifier. Ville Ojansivu, Nina Linder, Esa Rahtu, Matti Pietikäinen, Mikael Lundin, Johan Lundin. Diagn Pathol. 2012, suppl. Lack of MMP-9 expression is a marker for poor prognosis in Dukes’ B colorectal cancer. Koskensalo S, Hagström J, Linder N, Lundin M, Sorsa T, Louhimo J, Haglund C. BMC Clin Pathol. 2012 Dec 7 External research funding: Sigrid Jusélius Foundation, Cancer Society of Finland. The group is also involved in infrastructure programmes: Biocenter Finland (Translational Research/Biobank Technologies), Biomedinfra (ELIXIR, BBMRI and EATRIS collaboration)

32 • FIMM Group Verschuren Lung Cancer Model Systems

FIMM-EMBL Group Leader (supported by the Orion-Farmos Research Foundation and Sigrid Jusélius Foundation) Emmy Verschuren, PhD

he aim of our research team is the study and elucidation of new strategies for lung Tcancer intervention, the leading cause of cancer mortality. Personalised medicine approaches to lung cancer face big challenges: diagnoses are typically made when the disease is already metastatic, and cancer cell populations are heterogeneous. This complicates molecular profiling on small biopsies, and forms the molecular basis of induced resistance to targeted therapies. New methods to study the causes Group Members: of lung cancer and inform the design of novel treatment options are therefore of crucial importance. With this in mind, we are continuing our active participation PI: Emmy Verschuren in the EU public-private IMI-PREDECT project, coordinated by E. Verschuren on the Postdoctoral Researchers: Katja Närhi, Dat Nguyen academic side, to generate sufficiently complex cultures of the three most common PhD Students: Jenni Lahtela, Rita Matos, solid tumours for target validation purposes. To this end, our lab is establishing Ashwini Nagaraj organotypic lung explant models, enabling measurement of stem cell fate, viability, Undergraduate Students: Nitai Peled, Elina Parri cell architecture and immune responses. These models also serve as an ultimate in Technician: Annabrita Schoonenberg vitro system to systematically validate lung cancer gene and pathway functions. Research projects in the lab study a variety of cell biological and biochemical properties of key genes or pathways commonly altered in human lung disease. Our major goal is to integrate expertise in both human and functional biology to create versatile mouse cancer models, matched with patient cohorts, for discovery of biomarkers or therapeutically targetable events. As an example, we identified frequent functional inactivation of the EPHA3 receptor tyrosine kinase protein in lung adenocarcinomas, and are currently studying its precise role in cancer susceptibility in vivo. Our approach utilises pathological read-out of disease to comprehensively model complex pathway interplay and heterogeneity, which directly impacts on drug response and drug resistance.

Key Publications: Lahtela J., Corson L B., Hemmes, A., Brauer, M.J., Koopal, S., Lee, J., Hunsaker, T. L., Jackson, P.K. and Verschuren, E.W. A High-Content cellular senescence screen identifies candidate tumor suppressors including EPHA3. Cell Cycle. 2013; 12(4): 625-34. Peart, M.J., Pyurovsky, M.V., Ulrist M., Verschuren, E.W., Jackson, P.K. and Prives, C. APC/CCdc20 targets E2F1 for degradation in prometaphase. Cell Cycle. 2010; 9: 3956-64.. Verschuren, E.W., Ban, K.H., Masek, M.A., Lehman, N.L. and Jackson, P.K.. Loss of Emi1-dependent APC/C inhibition deregulates E2F target expression and elicits DNA damage-induced senescence. Mol. Cell. Biol. 2007;27: 7955-65. Verschuren, E.W., Hodgson, J.G., Gray, J.W., Kogan, S., Jones, N. and Evan, G.I. The role of p53 in suppression of KSHV cyclin-induced lymphomagenesis. Cancer Res. 2004;, 64: 581-589. External research funding: Orion Farmos Research Foundation, Sigrid Jusélius Foundation, Helsinki Biomedical Graduate Program (HBGP), Marie Curie EU-FP7 IRG: SYSTUMS, FCT, Biocenter Finland emerging technologies: LentiGEMM, Innovative Medicines Initiative Joint Undertaking (IMI- JU): PREDECT.

FIMM • 33 Group Wennerberg Chemical Biology of Cancer

FIMM-EMBL Group Leader (supported by Jane and Aatos Erkko Foundation) Krister Wennerberg, PhD

espite a tremendous progress in identifying mutations and other genetic Dalterations associated with different cancer types and an increasing number of targeted cancer-selective drugs in the clinic, we still lack targeted and safe and effective therapeutic strategies for the majority of cancers. Our research aims to address the cancer druggability problem by screening for personalised and selective sensitivities to approved and investigational drugs among Group Members: primary cancer samples and cell lines, as well as by developing of proof-of-principle PI: Krister Wennerberg small molecule inhibitors (tool compounds) targeting promising novel molecular Senior Researchers: Gretchen Repasky, Leena Karhinen cancer targets. PhD Students: Arjan van Adrichem, Meri Kaustio In 2012, a major effort of the group was focused on the Leukaemia Personalised (rotation Sept-Nov), Muntasir Mamun Majumder Medicine programme between several FIMM research groups and HUCH. For (co-supervised with Jonathan Knowles), Tea Pemovska, this program and other projects, we developed and explored the cancer cell Drug Agnieszka Szwajda (co-supervised with Sensitivity and Resistance Testing (DSRT) platform and analysis together with the Tero Aittokallio) High Throughput Biomedicine Unit and the Aittokallio Group. This work and platform Masters Student: Sawan Kumar Jha has had a major impact on the research at FIMM and elsewhere with over 300 samples and cell lines screened to date and several articles submitted or in preparation. Within the Leukaemia PM programme, data from the DSRT platform is guiding therapy for our clinical collaborators. Furthermore, we are using the data to functionally stratify patient samples and to identify the underlying signals that drive the cancers. We had active collaborations with the Aittokallio Group at FIMM and the group of Samuel Kaski at Aalto University/HIIT to explore new experimental/computational strategies to predict drug and drug combination responses and to understand the biology behind drug responses. A proof of the progress in these collaborations came when our team won the NCI-DREAM breast cancer cell line drug response challenge in a worldwide competition with 47 other teams. Work on discovering tool compounds that inhibit novel cancer targets continued with screening for inhibitors of MgcRacGAP by support from the NIH Molecular Libraries Program. Looking forward, we will develop and continue to use the DSRT platform and other methods to gain a better understanding of individualized cancer dependencies and druggabilities and we will explore the identification of personalised small molecule inhibitor tools targeting cancer-specific mutated alleles discovered in our personalised medicine program collaborations.

Key Publications: Khan SA, Faisal A, Mpindi JP, Parkkinen JA, Kalliokoski T, Poso A, Kallioniemi OP, Wennerberg K, Kaski S. Comprehensive data-driven analysis of the impact of chemoinformatic structure on the genome-wide biological response profiles of cancer cells to 1159 drugs. BMC Bioinformatics. 2012 May 30;13:112. Koskela HL, Eldfors S, Ellonen P, van Adrichem AJ, Kuusanmäki H, Andersson EI, Lagström S, Clemente MJ, Olson T, Jalkanen SE, Majumder MM, Almusa H, Edgren H, Lepistö M, Mattila P, Guinta K, Koistinen P, Kuittinen T, Penttinen K, Parsons A,Knowles J, Saarela J, Wennerberg K, Kallioniemi O, Porkka K, Loughran TP Jr, Heckman CA, Maciejewski JP, Mustjoki S. Somatic STAT3 mutations in large granular lymphocytic leukemia. N Engl J Med. 2012 May 17;366(20):1905-13. Manuvakhova MS, Johnson GG, White MC, Ananthan S, Sosa M, Maddox C, McKellip S, Rasmussen L, Wennerberg K, Hobrath JV, White EL, Maddry JA, Grimaldi M. Identification of novel small molecule activators of nuclear factor-κB with neuroprotective action via high-throughput screening. J Neurosci Res. 2011 Jan;89(1):58-72. Zhang L, Nebane NM, Wennerberg K, Li Y, Neubauer V, Hobrath JV, McKellip S, Rasmussen L, Shindo N, Sosa M, Maddry JA, Ananthan S, Piazza GA, White EL, Harsay E. A high-throughput screen for chemical inhibitors of exocytic transport in yeast. Chembiochem. 2010 Jun 14;11(9):1291-301. External research funding: Jane and Aatos Erkko Foundation, NIH Molecular Libraries Program, Helsinki Biomedical Graduate Program (HBGP), FinPharma Doctoral Program – Drug Discovery (FPDP-D)

34 • FIMM Finland Distinguished Professors at FIMM

he idea of the FiDiPro - Finland Distinguished Professor – Programme, led and financed by the Academy of Finland and Tekes, Tthe Finnish Funding Agency for Technology and Innovation, is to facilitate the cooperation of international distinguished researchers with Finnish academic researchers. Currently, FIMM is enjoying the unprecedented benefits of a situation where there are three FiDiPro appointments at the institute.

Professor Jonathan K.C. Knowles, the former Head of Group Research at Roche, was selected to the FiDiPro position in 2010, Professor Juni Palmgren from Stockholm University and Karolinska Institutet, Sweden in 2011 and Professor Leif Groop from the Lund University Diabetes Centre last autumn. Jonathan Knowles is a dynamic pioneer of the personalised medicine field. Juni Palmgren is an internationally recognised statistical epidemiologist and Leif Groop is one of the world’s best-known diabetes researchers.

The presence of such world renowned leaders at FIMM is obviously no coincidence. The goal of FIMM is to put Finland at the international forefront of research in personalised medicine, and each of these FiDiPro appointments strengthens the ability of the institute to achieve this goal.

One example of where the FiDiPros are instrumental in FIMM activities is the detailed genetic and molecular understanding of diseases, which represents both a challenge and an opportunity, as it changes disease taxonomy and the foundation on how medicine is practiced. This is very well summarized in the following citation of Juni Palmgren in an interview done by Päivi Lehtinen in 2011. ”Over the coming years, new insights will be gained into the complex multifactorial mechanisms underlying human health, with consequences for prevention, early detection, treatment and cure. I see FIMM as being internationally one of the key players with a central role in both developing research infrastructures in Finland, and using the facilities for molecular medicine research on highest level.”

The research project of Leif Groop, the most recent FIMM FiDiPro, will combine state-of- the-art genetic methods with analyses of the special features of the Finnish population to tackle the mechanisms behind type 2 diabetes. In his interview, also done by Päivi Lehtinen, he said that “Diagnoses and monitoring are based on the measurement of blood glucose levels. The introduction of other biogenetic markers improves the accuracy of diagnoses and helps determine the treatment response and risks of side effects, enabling treatment to be tailored individually. In other words, the treatment of this disease is also trending towards personalised medicine.”

Photo by Veikko Somerpuro

FIMM • 35 Doctoral Training

At FIMM, PhD students play a highly important role in our research community. Sixteen doctoral students defended their theses and earned their degrees from 2009–2012, during FIMM’s build-up phase.

Specifically, FIMM celebrated seven dissertations in 2012:

Taru Tukiainen: “Metabolomics meets genetics – from an NMR metabolomics platform to the genetic architecture of serum metabolites” Supervisors: Samuli Ripatti and Kimmo Kaski, Aalto University

Anu Näkki: “Search for susceptibility genes in osteoarthritis” Supervisors: Janna Saarela, FIMM and Urho Kujala, University of Jyväskylä

Mia-Lisa Schmiedt: “The CLN5 disease: protein maturation, trafficking and pathology” Supervisors: Anu Jalanko and Aija Kyttälä, THL and FIMM

Henrik Edgren: “Bioinformatic identification of genomic Alterations in breast cancer” Supervisor: Olli Kallioniemi, FIMM

Elina Salmela: “Genetic structure in Finland and Sweden: aspects of population history and gene mapping” Supervisors: Päivi Lahermo, FIMM and Juha Kere, Karolinska Institutet

Tero Hiekkalinna: “On the superior power of likelihood-based linkage disequilibrium mapping in large multiplex families compared to population based case-control designs” Supervisors: Leena Peltonen-Palotie, Joseph Terwilliger, Columbia University and FIMM and Markus Perola, THL and FIMM

Juho Konsti: “Automated Image Analysis of Cancer Tissue Adapted for Virtual Microscopy” Supervisor: Johan Lundin, FIMM

In addition, the following dissertation was completed at the University of Turku:

Sirkku Pollari: “Dissecting the molecular mechanisms of breast cancer bone metastasis for therapeutic targeting” University of Turku, FIMM Supervisor: Olli Kallioniemi

FIMM’s 16 dissertations and their research supervisors, 2009–2012, visually represented Credit: Tagxedo.com

36 • FIMM The completion of these dissertations was balanced by the entry of several new PhD students to FIMM research groups, maintaining the total number of doctoral students at FIMM at just over 40, with approximately equal numbers of international and Finnish students. In the autumn, FIMM celebrated the admission of six students into Finnish doctoral programmes, including the Helsinki Biomedical Graduate Program (HBGP) and Helsinki Graduate Program in Biotechnology and Molecular Biology (GPBM). In addition, FIMM research groups maintained strong training relationships with several doctoral programmes nationally and locally in Helsinki:

• Helsinki Biomedical Graduate Program (HBGP) • Helsinki Graduate Program in Biotechnology and Molecular Biology (GPBM) • National Doctoral Programme of Advanced Diagnostic Technologies and Applications (DIA-NET) • FinPharma Doctoral Program (FPDP) • National Doctoral Programme in Informational and Structural Biology (ISB) with more than half of the doctoral students as selected members in these doctoral programs.

The year 2012 was the third year of the FIMM- EMBL International PhD Training Initiative (IPTI), bringing two new, outstanding doctoral students to the institute. Alok Jaiswal from India and Meri Kaustio from Finland, were selected as the top <1% candidates from a strong and large international applicant pool. Alok and Meri joined FIMM in late August and after a few days of orientation began their first research rotation. All of the FIMM-EMBL IPTI and numerous other doctoral students from FIMM participated in the EMBL International PhD Symposium, an annual training session at the EMBL (Heidelberg, Germany), in November 2012.

FIMM was engaged in several other aspects of doctoral training throughout the year. For example, the EU FP7 Marie Curie Initial Training Network (ITN) PRO-NEST continued as planned. In addition, the Biocenter Finland International Visitor Program was continued whereby several doctoral students and postdoctoral researchers from abroad joined FIMM to drive various research activities. This Biocenter Finland programme concluded at the end of 2012.

FIMM continued in the EU-, Finnish-, and City of Helsinki-funded PhDs to Business Life project coordinated by Culminatum Innovation, Ltd. This project aims to train PhD students and postdoctoral researchers in business principles, career coaching, and project management with the ultimate goals of enhancing collaborations between doctoral programmes and business, as well as readying doctoral students for careers in industry. In addition to participation of students and postdoctoral researchers in the courses, FIMM has a position on the Advisory Board to help steer the program development and future.

FIMM • 37 In late 2012, the FIMM early-stage research community was strengthened by the establishment of the FIMM Student and Postdoc Council. After peer nominations and voting, the Council members appointed were PhD students Poojitha Kota Venkata (Group Kallioniemi), Jenni Lahtela (Group Verschuren), and Tiia Luukkonen (Group Palotie) and postdocs Leena Karhinen (Group Wennerberg), Pauliina Munne (Group Kuznetsov), and Katja Närhi (Group Verschuren). This council is an institute-level initiative providing the student and postdoc community of FIMM with an umbrella structure under which to plan and coordinate events, a stronger collective voice at the institute, and greater visibility within and outside of FIMM. The council provides the organization needed to continue more effectively with several events underway, as well as the autonomy to explore and develop new ideas supporting student and postdoc research training. All students and postdocs at FIMM are welcome to bring new ideas, thoughts, and feedback to any council member and are highly encouraged to get involved in planning events.

Two previously arranged events that fall under the guidance of the Council are the FIMM Scientific Coffee Breaks and the annual PhD Student Poster Session. In the former, short talks are arranged twice a month for students, postdoctoral researchers, as well as senior researchers and group leaders to present their work for FIMM staff. In addition, the third annual FIMM poster session highlighted cutting edge research projects and collaborations. New initiatives now under the umbrella of the council include the NMMN Young Investigators Collaboration working to enhance inter- node activities in the Nordic EMBL Partnership and planning of the FIMM Symposium. The Council will officially begin its activities in early 2013.

Finally, during 2012, we thanked Leena Karhinen for her service to the institute in the role of interim research training coordinator and welcomed Gretchen Repasky officially back to the post.

38 • FIMM Technology Centre Overview

Research Director Janna Saarela

IMM Technology Centre is a national and international research core unit providing an extensive spectrum Fof biomedical research services. FIMM technology centre operates seven core units with a total of 46 technology experts from diverse educational backgrounds being involved in the operations. Technology Centre develops methods and offers services in the areas of genomics (sequencing, genotyping, expression, methylation and CNV profiling), high throughput biomedicine (screening of chemical compounds, approved drugs, and siRNA, as well as serum, cell and protein lysate microarrays), metabolomics, bioinformatics and IT services using state-of-the-art technologies. During 2012, we also initiated setting up translational research technologies, such as biomarkers and imaging and clinical informatics technologies developed by Dr. Johan Lundin’s group, as services. FIMM Technology Centre operates in close collaboration with the Biocenter Finland infrastructure networks and is strongly involved in the European Research Infrastructure (ESFRI) networks (EATRIS, EU-OPENSCREEN, BBMRI). The Centre was supported by Biocenter Finland as a part of the Genome- wide methods, Translational research (DDCB, Biobank), Proteomics and Metabolomics, and Bioinformatics networks, the Academy of Finland (EATRIS), the European Regional Development Fund (for the LifeMarkers project), and the Systems Microscopy Network of Excellence project. In 2012, we completed altogether over 230 projects serving or collaborating with tens of research groups from over 40 national and international universities and research institutes, including all Biocenter Finland universities, as well as from a few companies. Technology Centre continued developing the personalised medicine activities in FIMM by providing fast-track services for exome, transcriptome and genome sequencing and drug sensitivity and resistance profiling of patient samples. Further development of clinical profiling services and efficient integration of the comprehensive profiling data is our major development focus.

FIMM • 39 Genomics Unit

he Genomics Unit of the FIMM Technology Centre is the only nationwide centre Tthat offers high-throughput genotyping, gene expression and DNA methylation analysis services in Finland. In 2012, the Unit produced 634 million genotypes or gene expression and methylation analysis results over 30,600 DNA or RNA samples utilizing Illumina’s iScan, Sequenom MassArray, Roche Light Cycler 480 and ABI 3730XL platforms. These projects included whole genome SNP genotyping with six different microarray types, fine mapping with three different methods on three different organisms, methylation analysis, gene expression analysis of human and mouse samples, and cell line authentication services. Methylation analysis and cell line authentication services launched in 2011 were well appreciated by the research community. The genotyping unit was involved in 72 service and/or collaborative projects from national and international universities. In addition to high quality and high-throughput laboratory services, the Genomic Unit offered expertise in project planning, data handling and analysis. The focus in our internal development was placed on further strengthening our database tools in close collaboration with the data management unit. During 2012, there were major changes in personnel, both geneticist Mari Kaunisto and Päivi Lahermo embarked new avenues and were substituted by Senior Researcher Kati Donner (docent, PhD) and Postdoctoral Researcher Mervi Kinnunen (PhD).

Publications utilizing Genomics services in 2012: Sandholm N, Salem RM, McKnight AJ, Brennan EP, Forsblom C, Isakova T, McKay GJ, Williams WW, Personnel: SadlierDM, Mäkinen VP, Swan EJ, Palmer C, Boright AP, Ahlqvist E, Deshmukh HA, Keller BJ, Huang Contact Persons: Senior Researcher Kati Donner and H, Ahola AJ,Fagerholm E, Gordin D, Harjutsalo V, He B, Heikkilä O, Hietala K, Kytö J, Lahermo P, Postdoctoral Researcher Mervi Kinnunen Lehto M, Lithovius R,Osterholm AM, Parkkonen M, Pitkäniemi J, Rosengård-Bärlund M, Saraheimo M, Sarti C, Söderlund J,Soro-Paavonen A, Syreeni A, Thorn LM, Tikkanen H, Tolonen N, Tryggvason Senior Researcher Päivi Lahermo (on personal leave as K, Tuomilehto J, Wadén J, GillGV, Prior S, Guiducci C, Mirel DB, Taylor A, Hosseini SM; DCCT/EDIC of October 2012) and Postdoctoral Researcher Research Group, Parving HH, RossingP, Tarnow L, Ladenvall C, Alhenc-Gelas F, Lefebvre P, Rigalleau Mari Kaunisto (new appointment at FIMM as of August V, Roussel R, Tregouet DA, Maestroni A,Maestroni S, Falhammar H, Gu T, Möllsten A, Cimponeriu 2012) D, Ioana M, Mota M, Mota E, Serafinceanu C,Stavarachi M, Hanson RL, Nelson RG, Kretzler M, Senior Laboratory Technicians: Sirkka Ekström, Colhoun HM, Panduru NM, Gu HF, Brismar K, Zerbini G,Hadjadj S, Marre M, Groop L, Lajer M, Bull Annika Korvenpää and Anu Yliperttula SB, Waggott D, Paterson AD, Savage DA, Bain SC, Martin F,Hirschhorn JN, Godson C, Florez JC, Groop PH, Maxwell AP. New susceptibility loci associated with kidney disease in type 1 diabetes. PLoS Genet. 2012 Sep;8(9) Statistics on 2012 services: Number of genotypes or expression/ Holmberg V, Onkamo P, Lahtela E, Lahermo P, Bedu-Addo G, Mockenhaupt FP, Meri S. Mutations methylation data points produced: ofcomplement lectin pathway genes MBL2 and MASP2 associated with placental malaria. Malar J. 634 million 2012 Mar2;11:61.Parmar, AS, Alakulppi N, Paavola-Sakki P, Kurppa K, Halme L, Farkkila M, Turunen U, Lappalainen M, KontulaK, Kaukinen K, Maki M, Lindfors K, Partanen J, Sistonen P, Matto J, Number of samples genotyped with Wacklin P, Saavalainen P, Einarsdottir E. Association study of FUT2 (rs601338) with celiac disease and genome-wide SNP arrays: 680 inflammatory bowel disease in the Finnish population. Tissue Antigens. 2012 Dec;80(6):488-93. Number of samples genotyped with Surakka I, Whitfield JB, Perola M, Visscher PM, Montgomery GW, Falchi M, Willemsen G, de Geus targeted SNP arrays: 29,750 EJ,Magnusson PK, Christensen K, Sørensen TI, Pietiläinen KH, Rantanen T, Silander K, Widén E, Muilu Number of samples profiled with J,Rahman I, Liljedahl U, Syvänen AC, Palotie A, Kaprio J, Kyvik KO, Pedersen NL, Boomsma DI, Spector genome-wide expression arrays: 140 T,Martin NG, Ripatti S, Peltonen L; GenomEUtwin Project. A Genome-Wide Association Study of Number of cell lines authenticated: 51 MonozygoticTwin-Pairs Suggests a Locus Related to Variability of Serum High-Density Lipoprotein Cholesterol. Twin ResHum Genet. 2012 Dec;15(6):691-9. Tollenaere C, Susi H, Nokso-Koivisto J, Koskinen P, Tack A, Auvinen P, Paulin L, Frilander MJ, Lehtonen Services provided by the Genomics Unit: R,Laine, AL. SNP Design from 454 Sequencing of Podosphaera plantaginis Transcriptome Reveals a • Targeted and genome-wide SNP genotyping GeneticallyDiverse Pathogen Metapopulation with High Levels of Mixed-Genotype Infection. PLoS • Targeted and genome-wide microsatellite One. 2012;7(12).Hytönen MK, Arumilli M, Lappalainen AK, Kallio H, Snellman M, Sainio K, Lohi H. A genotyping Novel GUSB Mutation inBrazilian Terriers with Severe Skeletal Abnormalities Defines the Disease as • Expression profiling on microarrays Mucopolysaccharidosis VII. PLoSOne. 2012;7(7). • Targeted and genome-wide methylation Alasaari JS, Lagus M, Ollila HM, Toivola A, Kivimäki M, Vahtera J, Kronholm E, Härmä M, Puttonen S, profiling Paunio T.Environmental stress affects DNA methylation of a CpG rich promoter region of serotonin • Cell line authentication transporter gene in anurse cohort. PLoS One. 2012;7(9):e45813.10.3

40 • FIMM Sequencing Unit

equencing Unit is a national and international service provider for next generation Ssequencing (NGS) and capillary sequencing services. The Sequencing Unit has been operating in the NGS field with Illumina sequencing-by-synthesis technology since 2008. The capillary sequencing services had another steady and successful year while the demand for NGS services kept on escalating. In 2012, the Unit provided a wide variety of sequencing services for 65 principal investigators from more than 20 institutes and companies, many of them as international collaborations. To address the increased demand in NGS services, we invested both to higher and faster sequencing capacity. In April, Illumina MiSeq Personal Sequencer was installed to complement existing HiSeq2000 capacity. MiSeq enabled not only feasible, small scale pilot projects and a variety of R&D experiments, but also significantly reduced the turnaround time for deep amplicon sequencing for mutation detection. By the end of the year, a rapid, genome scale sequencing platform HiSeq1500 was also installed. HiSeq1500 platform accelerates the sequencing of human genomes significantly by reducing the sequencing time from fourteen to two days. We saw growth in all sequencing applications, but transciptome analysis (RNA-Seq) and deep PCR amplicon sequencing (Amplicon-Seq) were the ones with Personnel: the largest increase in demand. In collaboration with a wide range of life scientists, Contact Persons: Head of Laboratory Pekka Ellonen, altogether 226 transcriptomes from nine different species were profiled. Amplicon- Senior Researcher Pirkko Mattila Seq is a sensitive approach to study clonal structure of somatic mutations in highly Senior Laboratory Technicians: Sari Hannula, sensitive resolution. Amplicon-Seq was successfully utilized for example to detect of Maija Lepistö, Sonja Lagström recurrent mutations in large granular lymphocytic leukaemia patients (Koskela et al. Laboratory Analysts: Tiina Hannunen, Aino Palva, NEJM). Development of bioinformatic analysis packages for RNA-seq and Amplicon- Anna Kossila Seqin collaboration with Bioinformatic unit facilitated the increased throughput for Trainee: Oskari Torppa both applications. The Sequencing Unit continued participating in the Personalised medicine Statistics on 2012 services: program by performing molecular profiling of patient samples. Altogether 22 patient cases were profiled with deep exome sequencing and transcriptome analysis. NGS SERVICES 2011 2012 GROWTH Altogether 290 human exomes were sequenced and a similar number of exomes PROJECTS 87 142 163 % has already been ordered for the coming year. The success in exome sequencing has TOTAL NGS LIBRARIES 838 933 111 % brought about a new clientele with new needs: the need for clinical re-sequencing, DNA LIBRARIES 722 701 97 % especially exome sequencing with clinical reporting, has become evident. This important translational service will be a major development focus of the Sequencing RNA LIBRARIES 116 226 195 % unit for the coming year. smallRNA LIBRARIES 2 26 1300 % In our fifth year of NGS operations, we saw the rise of systemic utilization of NGS NGS Amplicons 76 2070 2724 % methodology in research. Within the same research projects, samples are more and more profiled in several levels: DNA sequence structure and variation, expressed RNA Services provided by the Sequencing Unit: and microRNA profiles and epigenetic modification levels (methylation sequencing). • Capillary sequencing services (Full Service, We continue developing and fine-tuning laboratory workflows and bioinformatic Ready-to-Run, fragment analysis) analysis packages towards a comprehensive systems biology approach together with • Genomic DNA libraries other FIMM Tech Centre units. • Transcriptome libraries Selected publications where the sequencing unit contributed: • small-RNA libraries • mtDNA libraries Luukkonen TM, Pöyhönen M, Palotie A, Ellonen P, Lagström S, Lee JH, Terwilliger JD, Salonen R, Varilo T. Abalanced translocation truncates Neurotrimin in a family with intracranial and thoracic • Custom targeted enrichment aortic aneurysm. J Med Genet. 2012 Oct;49(10):621-9. • Amplicon sequencing Koskela HL, Eldfors S, Ellonen P, van Adrichem AJ, Kuusanmäki H, Andersson EI, Lagström S, • Exome sequencing Clemente MJ, Olson T, Jalkanen SE, Majumder MM, Almusa H, Edgren H, Lepistö M, Mattila P, Guinta • Cancer mutation panels K, Koistinen P,Kuittinen T, Penttinen K, Parsons A, Knowles J, Saarela J, Wennerberg K, Kallioniemi O, • Whole genome sequencing Porkka K, LoughranTP Jr, Heckman CA, Maciejewski JP, Mustjoki S. Somatic STAT3 mutations in large • Targeted methylation sequencing granular lymphocyticleukemia. N Engl J Med. 2012 May 17;366(20):1905-13. Tyynismaa H, Sun R, Ahola-Erkkilä S, Almusa H,Pöyhönen R, Korpela M, Honkaniemi J, Isohanni P, Paetau A, Wang L, Suomalainen A. Thymidine kinase 2 mutations in autosomal recessive progressive externalophthalmoplegia with multiple mitochondrial DNAdeletions. Hum Mol Genet. 2012 Jan 1;21(1):66-75.

FIMM • 41 High Throughput Biomedicine

he High Throughput Biomedicine Unit of the Technology Centre was formed in T2012 by the merger of the Chemical Biology and the RNAi units. As the name implies, the new Unit is set up to handle a wide range of biomedical high throughput assays with a strong foundation in RNAi and chemical screening. It is operating as a local, national and international research infrastructure. Support comes from Biocenter Finland through both the Genome-Wide Methods network and the “Drug Discovery and Chemical Biology” (DDCB) platform of the Translational Technologies network. The national DDCB platform is also coordinated at the unit. Furthermore, the unit is involved in several EU-level infrastructures and projects, including EU- OPENSCREEN (Finnish partner), EATRIS (national coordinator of Small Molecule product group) and the Systems Microscopy Network of Excellence project. The Unit provides high throughput assay services of many types such as chemical Personnel: screens against large chemically diverse libraries for chemical probe/lead discovery Contact Person, PI: Krister Wennerberg screens against targeted bioactive collections for bioprofiling purposes, genome- Senior Researchers: Jani Saarela, Vilja Pietiäinen, wide or targeted siRNA screens and array printing and associated analysis. Assays are Päivi Östling, Heidi Virtanen (EU-OPENSCREEN) performed in multi-well plates (96-, 384- or 1536-well formats) or high density array Postdoctoral Researcher: Carina von Schantz-Fant formats. The Unit manages two screening laboratories; one self-service facility that contains the equipment to perform small chemical and genetic screens on a semi- Coordinator: Laura Turunen automated basis and one fully automated state-of-the-art HTS laboratory with two Assay developer: Evgeny Kulesskiy robotic systems, a high content screening microscope and a microarray printer. To Senior Laboratory Technicians: support the use of the screening facilities, the unit maintains a chemical collection of Anna Lehto, Ruusu-Maaria Merivirta, 140,000 compounds and a genome-wide human siRNA library. Ida Lindenschmidt, Karoliina Laamanen, In 2012, the new Unit handled a wide array of projects and more than 160 screens Marika Karjalainen (until August 2012) in 28 different user-driven projects were completed. A continued important capacity Bioinformatician: Swapnil Potdar of the Unit was to provide drug sensitivity and resistance screens with oncology compounds on both patient samples and cancer cell lines (140 completed within Statistics on 2012 services: the Unit and compound plates for another 254 screens provided directly to users). Important initiatives that were initiated in 2012 included the sharing of best-in-class Number of projects: 28 compounds, the ability to cherry-pick compounds or siRNAs from the full library for Number of screens: 160 targeted screens and a collaborative agreement with Labcyte Inc. on the exploration Number of plates with assay-ready drugs and advancement of the use of Echo acoustic dispenser technologies. and siRNAs provided to users: 408 Publications utilizing the services of the unit: Koskela HL, Eldfors S, Ellonen P, van Adrichem AJ, Kuusanmäki H, Andersson EI, Lagström S, Services provided by the HTB Unit: Clemente MJ, Olson T, Jalkanen SE, Majumder MM, Almusa H, Edgren H, Lepistö M, Mattila P, Guinta • Assay guidance and optimization K, Koistinen P, Kuittinen T, Penttinen K, Parsons A,Knowles J, Saarela J, Wennerberg K, Kallioniemi O, • Chemical screening Porkka K, Loughran TP Jr, Heckman CA, Maciejewski JP, Mustjoki S. Somatic STAT3 mutations in large granular lymphocytic leukemia. N Engl J Med. 2012 May 17;366(20):1905-13. • siRNA screening • Drug sensitivity and resistance testing Denisova OV, Kakkola L, Feng L, Stenman J, Nagaraj A, Lampe J, Yadav B, Aittokallio T, Kaukinen P, Ahola T, Kuivanen S, Vapalahti O, Kantele A, Tynell J, Julkunen I, Kallio-Kokko H, Paavilainen H, • Cell-based assays Hukkanen V, Elliott RM, De Brabander JK, Saelens X, Kainov DE. Obatoclax, saliphenylhalamide, and • Biochemical assays gemcitabine inhibit influenza a virus infection. J Biol Chem. 2012 Oct 12;287(42):35324-32. • Array printing • Lysate microarrays • Serum microarrays • Miniaturized assays • Preparation of assay-ready drug or siRNA plates • Test aliquots of best-in-class chemicals • Providing assay plates and reagents • High content imaging and image analysis

42 • FIMM Metabolomics Unit

etabolomics is a discovery-driven field of science, which aims at the comprehensive Mquantitative analysis of all metabolites in any biological systems, their dynamics, composition, interactions, and responses to interventions or a specific physiological state. The mission of FIMM Metabolomics Unit is to identify metabolite biomarkers in several complex human diseases, which will help to understand the mechanism and to predict and prevent the disease at an early stage. We conduct quantitative and high- throughput targeted metabolite profiling of biological samples, i.e., serum, plasma, cell culture supernatants, cell lysates, tissues and C. elegans, etc. The Hamilton’s Microlab StarLine liquid handling system is used for automatic sample preparation, to increase the throughput and decrease the variations. The extracted metabolites are separated using Waters Acquity ultra high-pressure liquid chromatography (UPLC) by utilizing hydrophilic interaction liquid chromatography (HILIC) column for better separation of Personnel: polar metabolites. Metabolites are analysed using Waters XEVO-TQ-S triple quadrupole Contact Person, Head of the Unit: Vidya Velagapudi mass spectrometry with electrospray ionization (ESI) by employing the multiple Analytical Chemist: Jean-Christophe Yorke reaction monitoring (MRM) strategy in both positive and negative polarities. The raw data is imported and processed using TargetLynx software. Metabolite quantification Research Assistants: Vasudev Kantae, Bhargavi Carasala is done using both labeled internal and external calibration curves. Our developed method includes fast and single chromatographic conditions (fifteen min including equilibration time), requires a sample amount of 50–100 µl, offers sensitivity for trace level applications (pmol), and a wide coverage of individual metabolite concentrations in three orders of magnitude. High degree of selectivity Statistics on 2012 services: provided by MRM quantifies 94 polar metabolites from fifteen different classes (amino Number of samples analysed: 119 acids, neurotransmitters, sugars, organic compounds, nucleotides, nucleosides, bile acids, central carbon metabolites, urea cycle intermediates, etc.) with high quality of data analysis. Our services and technologies can be applied to research projects in many ways. The targeted metabolite profiling method has high potential for the discovery of the Services provided by the Metabolomics biomarkers for the disease risk, to meet the clinical demands. Unit: High-throughput targeted quantitative analysis of polar metabolites in: • Serum and plasma • Cells • Cell culture supernatants • Tissues • C. elegans

FIMM • 43 Bioinformatics and IT Unit

IMM’s computing infrastructure has been designed for scalability and flexibility Futilizing the latest information technologies, to enable us to meet the rapidly increasing storage and performance requirements of data driven research. During the year 2012, FIMM’s computing capacity, which is partly hosted at CSC - IT Center for Science Ltd, was increased by 25% (20% in 2011) to 1500 CPUs. In addition to the computing cluster, the IT infrastructure consists of more than hundred physical and virtual servers hosting bioinformatics applications and databases vital for biomedical research. In 2012, we installed 72TB new disk space for storing sequencing and bioinformatics analysis results. Overall, the local storage volume grew 22% in 2012 (35% in 2011). The experimental high performance flash memory file system piloted in 2011 with 1.2TB was upgraded in January to 7TB and in July to 13TB. In preparation for future storage volume growth, FIMM’s tape library for backup was upgraded from 450 TB to 1700 TB by replacing the old 4th generation tape drives with 6th generation drives. A major effort has been put in to automating the analysis work flows that need to happen after next generation sequencing. For example, the quality control and primary analysis of the exome sequencing data, including variant identification and annotation, now happen without action from a bioinformatician. The analysis was performed on 804 samples in 93 projects originating from 37 principal investigators. We are also close to automating the RNA sequencing data analysis. We also developed new methods and tools. We can now infer the chromosomal amplifications and deletions from the exome sequencing data. This is providing additional, very valuable insights into the disease mechanisms when analysing patient tumour samples in the context of personalised medicine and allows to get rid of a bespoke test for copy number variation. Further, in response to the Sequencing Unit starting to offer amplicon sequencing to assess the status of a narrow(er) set of target genes, e.g. genes often mutated in cancer, we also developed a pipeline to handle this data. Also, a browser based tool was developed for managing and analysing the data from cell line authentication analysis offered by the genotyping unit. With this, the user can upload the data files and easily see how well it matches with the reference data, as well as identify most similar cells lines in the reference library. In support of the FIMM biobanking activities, we continued to develop the SamWise laboratory information management system. Whereas originally intended to be used just for sample logistics information with rudimentary access control, it Personnel: can now also handle data interesting from the research perspective, e.g. phenotype Contact Person Bioinformatics: measurements and answers to questionnaires. We also started to implement a more Coordinator Imre Västrik fine-grained access control, which will also allow granting access only to selected Contact Person IT services: Head of IT Unit parts of the data. Timo Miettinen Activities in the GEN2PHEN program have continued. The data transfer Contact Person GEN2PHEN: Senior Researcher application framework for the Café Varome concept, developed at the University Juha Muilu of Leicester, has been finalised. Another activity during the year has been the development of a new version of the Finnish Disease Portal, consisting of data of Bioinformaticians: Henrikki Almusa, Henrik Edgren, Samuli Eldfors, Jesús María López Martí, disease mutations enriched in the Finnish population (http://findis.org). Disease Syed Arshi Uz Zaman mutations have been manually curated and positioned on the latest genome build and Locus Reference Genomic Sequence.In addition to these ”standard” analysis and Information system specialist: Kyösti Sutinen major development endeavours, we have also been involved in countless ”odd jobs”, IT Designers: Sari Bombino, Jani Heikkinen, ranging from recovering lost files to metagenomics analysis. Askar Ibragimov, Anne Leinonen (until August 2012), Teemu Perheentupa, Tomi Simonen, Kari Tuomainen, Hannu Turunen GEN2PHEN group: Senior Researcher Anne Polvi, IT Designers Myles Byrne and Tuomas Pellonperä

44 • FIMM Publications where the unit contributed: Nikolaev SI, Sotiriou SK, Pateras IS, Santoni F,Sougioultzis S, Edgren H, Almusa H, Robyr D, Guip- poniM, Saarela J, Gorgoulis VG, Antonarakis SE, HalazonetisTD. A single-nucleotide substitution mutator phenotyperevealed by exome sequencing of human colonadenomas. Cancer Res. 2012 Dec 1;72(23):6279-89. Koskela HL, Eldfors S, Ellonen P, van Adrichem AJ,Kuusanmäki H, Andersson EI, Lagström S, Clem- ente MJ, Olson T, Jalkanen SE, Majumder MM, Almusa H, Edgren H, Lepistö M, Mattila P, Guinta K, Koistinen P, Kuittinen T, Penttinen K, Parsons A, Knowles J, Saarela J, Wennerberg K, Kallioniemi O, Porkka K, Loughran TP Jr,Heckman CA, Maciejewski JP, Mustjoki S. Somatic STAT3mutations in large granular lymphocytic leukemia. N EnglJ Med. 2012 May 17;366(20):1905-13. Tyynismaa H, Sun R, Ahola-Erkkilä S, Almusa H,Pöyhönen R, Korpela M, Honkaniemi J, Isohanni P, Paetau A, Wang L, Suomalainen A. Thymidine kinase 2mutations in autosomal recessive progressive externalophthalmoplegia with multiple mitochondrial DNAdeletions. Hum Mol Genet. 2012 Jan 1;21(1):66-75. Byrne MG, Fokkema IF, Lancaster O, Adamusiak T, Ahonen-Bishopp A, Atlan D, Beroud C, Cornell M, Dalgeish R, Devereau A, Patrinos G, Swertz MA, Taschner PE, Thorisson GA, Vihinen M, Brookes AJ, Muilu J. VarioML framework for comprehensive variation data representation and exchange. BMC Bioinformatics. 2012 Oct 3;13(1):254. Adamusiak T, Parkinson H, Muilu J, Roos E, van der Velde KJ, Thorisson GA, Byrne M, Pang C, Gol- lapudi S, Ferretti V, Hillege H, Brookes AJ, Swertz MA. Observ-OM and Observ-TAB: Universal syntax solutions for the integration, search, and exchange of phenotype and genotype information. Hum Mutat. 2012 May;33(5):867-73.

Statistics on 2012 services: Number of genome sequence analyses: 804 Number of tumour – normal tissue pairs analyses: 48 Number of samples analysed for amplifications and deletions: 77 Number of gene expression quantification analyses: 128 mRNA and 26 miRNA samples

Services provided: • Identification and annotation of single nucleotide variants and small insertions and deletions in genome sequence data • Identification of disease-associated variants, e.g. in affected but not in healthy relatives, in tumour but not in normal tissue • Identification of deleted and amplified regions in genome • Gene expression quantification from RNA sequence data • Identification of fusion transcripts from RNA sequence data • Server and application hosting • High performance computing and bioinformatics analysis environment • End-user support for the computing cluster and bioinformatics applications • Custom software development

FIMM • 45 Biobanking

iobanks of human biological samples with associated medical data have become a vital resource in unravelling the aetiology of Bdiseases, identification and validation of new diagnostic methods, as well as advancing personalised medicine. As the new Finnish legislation on biobanking will come into force in September 2013 a whole range of new possibilities will become available. Biobanking can bridge basic, translational and clinical research, life-science industry, and help in the assessment of health care outcomes and efficiency. But realizing its full potential requires a change in the way we see biobanking; in addition to researcher driven projects, we should also aim at centralized and harmonized institutional level biobanking, where samples and data from consenting donors and patients are routinely collected into a biobank. And there is a change needed in the way we see the sample donors; we should encourage them to be active participants of the biobanks, and by utilizing the new wireless technologies, develop platforms that enhance the exchange of information between a biobank and a sample donor.

Meilahti Integrated Biobank Infrastructure (MIBI)

Today, the concept of biobanking has expanded from collecting and storing samples to a comprehensive and systematic approach to managing samples, patient data and data generated by deep molecular profiling. Individual research groups find it increasingly challenging to manage the whole biobanking process. Therefore, FIMM and THL joined forces in 2011 and created Meilahti Integrated Biobank Infrastructure, MIBI, which offers a wide range of biobanking services for all interested research projects collecting samples and data. MIBI has a leading role in national and international biobanking networks, the most important one being the BBMRI network. In addition to providing biobanking services, THL and FIMM are actively promoting the launch of new comprehensive sample collections and continue to contribute to the decade’s long tradition of collecting unique population sample cohorts. Especially the Meilahti campus is in the position to benefit from the largest patient pool in Finland and the Finnish researchers have been in the global front-line in the application of biobanks for decades. For example, the DNA sample archives of the National Institute for Health and Welfare (THL), FIMM partner institution on the Meilahti campus, cover samples from >200,000 individuals, all linked with detailed demographic and comprehensive long-term follow-up information.

Contact at FIMM: Head of Development: Kimmo Pitkänen

Contact at THL: Head of Public Health Genomics Unit, THL and Senior Scientis, FIMM: Anu Jalanko

Personnel: Head of Laboratory: Päivi Laiho Laboratory Coordinators: Minttu Sauramo (on personal leave), Tuuli Sistonen, Tiina Vesterinen Senior Researchers: Taija af Hällström, Aija Kyttälä, Tuomas Mirtti (FIMM/HUSLAB), Juha Muilu, Kaisa Silander Postdoctoral Researcher: Maija Puhka Laboratory and Research Technicians: Siv Knaappila, Sini Lähteenmäki, Elina Mäkinen, Anne Nyberg, Seija Puomilahti, Reija Randén-Brady, Minna Suvela, Arja Tapio, Arja Terola, Anne Vikman, Regis Wong Laboratory Engineer: Niina Eklund Information Systems Specialist: Kyösti Sutinen Systems Architect: Markku Laukkanen IT Specialist: Askar Ibragimov IT Designers: Timo Miettinen, Teemu Perheentupa, Tomi Simonen, Hannu Turunen

Note: with the word biobank, we refer to sample collections and matching clinical data from patients, not the concept of a formal biobank as defined by the new Finnish Biobank Law, which will come to effect in September, 2013.

46 • FIMM Integrated full-service biobanking

The MIBI infrastructure provides state-of-the- art sample processing and several technology platforms such as exosome isolation, iPS cell preparation, sample microarrays, multi-spectral imaging for molecular pathology, web microscopy, clinical informatics and databases.

Sample storage services

MIBI has liquid nitrogen (LN2) based sample storage facility which provides low-cost, secure and controlled storage of samples in the LN2 vapour phase. Currently, the system has the capacity to store 480,000 samples. This sample storage is available to all research groups on the campus and elsewhere for storing small and medium sized sample collections. In addition to LN2, samples can be stored in -20°C or room temperature when appropriate. During 2012, MIBI acquired an automated NitroStore storage system from Matrical. Setting up the device was initiated during 2012 and it will be fully operational during 2013. NitroStore consists of both -20°C and -80°C storage modules with a capacity to store 100,000 samples in both temperatures (in 0.5 ml vials). NitroStore will increase productivity by speeding up cherry picking of samples in the largest and most widely used biobanking projects.

Automated sample processing Contact Person: Head of Laboratory Päivi Laiho MIBI offers automated DNA extraction service from whole blood, buffy coats, cell and tissue samples, saliva and buccal swabs, as well as automated DNA aliquoting, including normalization and quality control. Similarly, liquid handling robotics allows automated serum and plasma aliquoting if needed. In 2012, as a major effort, MIBI participated in the collection of the FINRISK 2012 cohort of THL, this time collecting DNA and RNA samples from 5,834 individuals and leukocytes from 1,888 individuals. Additional projects included the Child-sleep project, a birth cohort for which the recruitment of families ended at the end of 2012, with a total of >1,500 participating parents-baby trios. Other large sample collections MIBI took part in were HUB and FHRB. Altogether, in 2012 MIBI extracted 10,700 DNA samples and produced 42,000 DNA aliquots for over 60 national and international research projects.

Biobank Informatics Contact Person: Senior Researcher Juha Muilu The biobank informatics group provides IT systems development services for the MIBI biobank and the National BBMRI.fi network, where the group is coordinating informatics working-package. One of the main activities during the year has been setting up centralized IT computing facility for the national node together with CSC, VSSHP and THL. The node provides a shared cloud instance hosting computing and database services, which can be accessed from affiliated biobanks using secure connections. Underlining database systems and applications have been installed on the pilot system and initial pathology datasets have been collected from TYKS, OYKS and HUB consisting of 0.4M samples with tissue and diagnosis information. Local database applications were developed and improved for handling biobank data related to the BBMRI and MIBI projects. The KITE, a fast database query engine developed in the IT systems group, has been developed further for BBMRI.fi use, in collaboration with ELIXIR’s EGA AAI pilot project lead by CSC which aims to develop a federated authentication and authorization system for the controlled access data. The developed application, called REMS, has been successfully integrated with the KITE system. The group has continued international collaboration with BBMRI Nordic. Workshops have been organized together with the Karolinska Institutet for harmonising informatics systems for the Nordic BBMRI nodes.

FIMM • 47 Contact Persons: Molecular pathology and imaging services Research Director Johan Lundin Laboratory Coordinator Tiina Vesterinen FIMM molecular pathology laboratory provides routine services for tissue-based research such as tissue processing, embedding, sectioning, and staining histochemically or by using immunohistochemical techniques. The laboratory offers also tissue microarray design and preparation which allows simultaneous analysis of large number of cases under standardized laboratory and evaluation conditions without significant damage to the original tissue block.Digital microscopy and imaging services are also provided. Stained microscopy slides can be digitized with an automated microscope scanner and stored as virtual slides on the WebMicroscope platform. The virtual slides comprise high-resolution images covering the entire specimen on the slide. With the WebMicroscopy applications virtual slides can be assessed visually or with assistance of automated image analysis.

Statistics on 2012 services: Number of TMA tissue punches: 1,108 Number of TMA blocks: 10

48 • FIMM On-going clinical biobanking projects

In 2012, FIMM continued to be active in building modern biobanks. With the word biobank, we refer to sample collections and matching clinical data from patients, not the concept of a formal biobank as defined by the new Finnish Biobank Law, which will come to effect in September 2013. Utilizing the integrated biobanking services of MIBI, two comprehensive samples collecting projects were expanding during 2012.

Finnish Hematology Registry and Biobank (FHRB) Contact Person: Head of Development Kimmo Pitkänen Finnish Hematology Registry and Biobank (FHRB) is a national research project for collecting a comprehensive set of samples from patients with haematological disorders. It is operated by three partners: The Finnish Association of Hematology (FAH), Finnish Red Cross Blood Service (FRCBS) and FIMM. Hospital District of Helsinki and Uusimaa and Pirkanmaa Hospital District were the first hospital districts to join and to utilize the project during 2012, and other three Finnish university hospitals will join the project during the beginning of 2013. During 2012, 133 patients were enrolled and they donated over 800 samples. FHRB is an open access biorepository and the access is granted based on published criteria. The list of currently available samples can be found at www.hematology.fi/fhrb.

Helsinki Urological Biobank (HUB) Contact Person: Laboratory Coordinator Tiina Vesterinen Helsinki Urological Biobank (HUB) is a joint project undertaking of FIMM and Hospital District of Helsinki and Uusimaa. Based on informed consent and by first ensuring the needs of diagnosis and treatment, the HUB project collects fresh frozen and formalin fixed paraffin embedded tissue samples together with blood and urine samples and broad clinical information. Samples are collected at the time of diagnosis and at follow-up visits. Sample collecting started in March 2012. During 2012, 492 patients gave their informed consent for sample donating, and the total amount of collected samples was over 470. The Tekes funded HUB biorepository will be open for all research and R&D studies which fulfil the access criteria. Criteria will be finalized during the beginning of 2013 and published on HUB’s website. More information: www.hubbiobank.fi.

FIMM • 49 Technology development at MIBI

Contact Person: Cell technologies Aija Kyttälä. Senior Scientist, THL & FIMM Cell technologies laboratory provide help for collecting, isolating and storing various cell samples for research purposes and for clinical projects. In 2012, peripheral blood mononuclear cells (PBMC) were collected and stored from 1,880 participants of the large Finnish population cohort study, Finrisk 2012. Fibroblast cultures were established from skin biopsies of 48 participants of FUSION – diabetes study. In collaboration with the Biomedicum Stem Cell Center, production of induced pluripotent stem cells (iPSC) from frozen PBMC samples was also established. IPS cells are artificial stem cells produced from somatic cells with enormous research potential, since they can be differentiated into various directions. The future goal of our laboratory is to develop iPS cell-based methods for utilization of previously stored samples and establish high-throughput techniques for iPS production.

Contact person: Tissue slice culture technologies Taija af Hällström, Senior Scientist MIBI has established tissue slice cultures (TSCs) from benign and malignant prostate tumour specimens to facilitate short-term functional studies. TSC are thin sections of tissues that can be maintained in culture for several days. TSCs are perhaps the most representative model of the human prostate cancer available, containing almost all of the cells typically present in the body, and maintaining essential epithelial-stromal interactions, as well as differentiated cells, which are typically lost in long-term primary cultures or cell-line models. TSCs can be used for functional genomic studies, cellular and tumour biology, as well as for drug response testing.

Contact person: Microvesicle technologies Maija Puhka, Postdoctoral Researcher Microvesicles are extracellular vesicles excreted by cells by two different mechanisms: exosomes are derived from the multivesicular bodies, whereas microparticles originate from direct budding of the plasma membrane. There has been an exponential interest in microvesicles due to their common ability to act as intercellular messengers or effectors targeting specific cell types or biological processes such as angiogenesis, tumour growth and metastasis. The vesicular cargo contains many biologically and diagnostically interesting molecules, including miRNA, mRNA, proteins and lipids that reflect the status of the secreting cell. We have optimized and validated protocols to extract microvesicles from the HUB-patient samples that can be used in research to find new biomarkers or reveal molecular pathology of the diseases.

50 • FIMM Building an infrastructure for cohorts’ sample and phenotype data

To facilitate the usage of these research cohorts, we have created during 2012 a web resource that contains information on available research cohorts with DNA samples (www.nationalbiobanks.fi). The web-pages include summarized information on available samples and phenotypes (http://www.nationalbiobanks.fi/ index.php/summary), genome-wide variation data (http://www.nationalbiobanks.fi/index.php/gwas) and short description and contact information for each cohort. Extensive epidemiological, genetic and biomarker studies have been performed using these cohorts. SamWise, the in-house developed laboratory information management system (LIMS) is used at MIBI for sample logistics. The SamWise secure database system has been expanded to include structured phenotype information accompanied by a rich set of metadata that could be searched using key words and reference library terms. Currently, the database stores 1,500 harmonized variables from 18,000 subjects from three large cohorts and several cohorts are under work.

Contact Person: Kaisa Silander, Senior Researcher

MIBI as part of the BBMRI.fi National Node

BBMRI.fi (Biobanking and Biomolecular Resources Research Infrastructure of Finland) (www.bbmri.fi) is a National Node of BBMRI-ERIC, operating under collaboration between THL, FIMM, university hospitals and universities. The national cohorts with DNA samples and associated data are an existing infrastructure of the National Roadmap of 2009 (National Biobanks of Finland), integrated into BBMRI.fi infrastructure. BBMRI.fi aims to create a harmonized, efficient and internationally leading biobank infrastructure providing strategic support to Finnish biomedical research, healthcare and biomedical industry. The on-going operations of BBMRI.fi are: • Build a National network of biobanks and operate it in collaboration with BBMRI-ERIC, BBMRI Nordic and European BBMRI National Nodes. • Maintain the leadership of Finnish scientists in the area of population biobanks by promoting access to population biobanks, offering tools for harmonization of data and samples and participating to international initiatives. • Bring the clinical biobanking efforts into the international forefront by building and piloting the operating model for hospital biobanks, harmonization of clinical data and samples and coordinating clinical biobanking projects. • Collaborate with National biomedical analysis services, such as BF and other ESFRIs. • Build a national biobank IT infrastructure serving biobanks, researchers, sample donors and authorities. • Continue to provide infrastructure services regarding sample collection, processing, storage and aliquoting for omics analyses. Coordinate standard operating procedures and quality control. • Provide ethical and legal services to the biobank community. • Promote public awareness of the potential of biobanking in biomedical research, advancement of population health and personalised medicine. • MIBI is an integral part of BBMRI.fi sample collection, processing and storage services, as well as development of the national Biobank IT infrastructure.

Contact Person: BBMRI-ERIC preparation and BBMRI.fi National Node Coordinator: Head of Public Health Genomics Unit, THL and Senior Scientist, FIMM: Anu Jalanko

FIMM • 51 Administration

FIMM Administration Unit and Project Management

The FIMM Administration Unit supports the Director in the management and development of the institute. The nature of FIMM as an international institute, along with the Nordic EMBL Partnership, and as a joint research institute at national level between the University of Helsinki, HUS, THL and VTT means that FIMM Administration Unit has close collaboration with the partnership institutes, partner organisations and ministries, as well as other stakeholders. The administrative functions are completely taking place in English. The size of the Unit has been stable during the start-up and construction phase of FIMM. In 2012, the Unit composed of six people (5,1 person years) taking care of administrative affairs. The initiative launched in 2011 of a joint appointment with the Research Sector of the University of Helsinki was considered successful and the intention is to continue collaboration beyond 2013. Within FIMM, the Administration Unit is collaborating closely with Coordinators in project management, education and training related affairs, as well as communications, e.g. in planning and implementation of the events mentioned in this report. In 2012, Senior Researcher Mari Kaunisto was appointed a part-time Communications Coordinator to promote communication of research results and personalised medicine to the general public and media. In 2012, the total budget of FIMM was 15.5 M€, with almost 70 % arising from competitive external funding. In the end of 2012, there were altogether almost 50 research and infrastructure projects, including twelve EU projects, ongoing and at the negotiation phase, two of them coordinated by FIMM. In addition, there were Administration Unit: projects funded by the Academy of Finland, Tekes, National Institutes for Health (NIH), as well as several foundations. The large share of external funding means Administrative Manager: Reetta Niemelä that there needs to be a well-functioning project management at the institute, with Human Resources Coordinator: Riitta Alatalo competence in coordinating large international consortia. In 2012, there were seven Senior Advisor: Mika Frederiksen (joint appointment Coordinators and other key persons playing a key role in research and infrastructure with the Research Sector of the University of Helsinki) projects funded with external funding. Department Secretary: Sanni Hypponen (personal leave, substitute Ella Westerlund) Financial Planning Officer: Riitta Koskinen Financial Manager: Marja Medina

Education, Communication and Project Management Coordinators: Project Secretary: Heidi Arling Tripepi Senior Researcher, Communications Coordinator: Mari Kaunisto Project Coordinators: Sari Kivikko, Huei-yi Shen, Birgit Simell Project Director: Kari Pitkänen Head of Development: Kimmo Pitkänen Senior Researcher, Research Training Coordinator: Gretchen Repasky Coordinator, PA to Director Kallioniemi and Prof. Knowles: Susanna Rosas Laboratory Coordinator: Virve Tiusanen Coordinator: Imre Västrik

52 • FIMM FIMM Board and SAB

The Board of FIMM 1.7.2010-31.3.2014

The Board of FIMM comprises of the Chair and nine members, each member having a personal deputy. The University of Helsinki appoints three members to the Board, and HUS, THL and VTT each name one member. In addition, the University invites a representative from an industry and the Biocenter Finland network. One member is appointed from among the Institute’s staff. The Board steers and supervises the Institute’s activities and finances, as well as approves the strategic plans, objectives, budget and human resources plan. The Board also issues statement on the Institute’s research directors and research group leaders based on international assessments.

Chair of the Board: Vice Rector, Professor Kimmo Kontula, University of Helsinki

Members of the Board:

Research Director, Professor Anna-Elina Lehesjoki, Neuroscience Center, University of Helsinki Professor Kimmo Porkka, Institute of Clinical Medicine, Faculty of Medicine, University of Helsinki Dean, Professor Risto Renkonen, Faculty of Medicine, University of Helsinki Head of Labotatory, Laboratory Manager Pekka Ellonen, FIMM Technology Centre (personnel) Chief Research Officer, ProfessorLasse Viinikka, HUS Deputy Director General, Professor Juhani Eskola, National Institute for Health and Welfare (THL) Vice President, Professor, R&D Biotechnology, Anu Kaukovirta-Norja, VTT Chief Executive OfficerPekka Mattila, Desentum Oy (industry) Director, Professor Eero Vuorio, Biocenter Finland (BF)

Deputy Members of the Board:

Research Director, Professor Irma Thesleff, Institute of Biotechnology, University of Helsinki Professor Annamari Ranki, Institute of Clinical Medicine, Faculty of Medicine, University of Helsinki Professor Kalle Saksela, Haartman Institute, Faculty of Medicine, University of Helsinki Senior Researcher, Coordinator of Research Training Gretchen Repasky, FIMM (personnel) Chief Administrative Physician, MD, PhD, LL.D., MFPM, Assistant Professor Lasse Lehtonen, HUS Senior Researcher, Head of Public Health Genomics Unit, Anu Jalanko, THL Technology Manager Richard Fagerström, VTT CEO Saara Hassinen, Strategic Centre for Health and Well-being, SalWe Oy (industry) Chair of the Board, Academy Professor Seppo Ylä-Herttuala, Biocenter Finland (BF)

Permanent Expert of the Board: Director, Professor Olli A. Jänne, Biomedicum Helsinki, University of Helsinki

FIMM • 53 The Board of FIMM 1.3.2007–30.6.2010

Chair of the Board: Chief Executive, Professor Marja Makarow, European Science Foundation, Strasbourg, France

Members of the Board:

Deputy Director General, Professor Juhani Eskola, THL Vice Rector, Professor Kimmo Kontula, Faculty of Medicine, University of Helsinki Research Director, Professor Anna-Elina Lehesjoki, Neuroscience Center, University of Helsinki Director, Professor Dan-Olof Riska, Helsinki Institute of Physics (HIP) Vice President, Professor, R&D Biotechnology, Anu Kaukovirta-Norja, VTT Vice President, Business Development, MD, PhD, EMBA Aino Takala, Orion Corporation Act. Medical Director, Chief Research Officer, ProfessorLasse Viinikka, HUS Docent Elisabeth Widén, FIMM Technology Centre

Deputy Members of the Board:

Research Professor Helena Kääriäinen, THL Professor Annamari Ranki, Faculty of Medicine, University of Helsinki Research Director, Professor Irma Thesleff, Institute of Biotechnology, University of Helsinki Vice Rector, Professor Heikki Mannila, Aalto University Technology Manager Kirsi-Marja Oksman-Caldentey, VTT Senior Vice President R&D, MD, PhD Reijo Salonen, Orion Corporation Chief Administrative Physician, M.D., PhD, LL.D., MFPM, Assistant Professor Lasse Lehtonen, HUS Laboratory Engineer Jouko Siro, FIMM Technology Centre

Permanent Experts of the Board:

Director, Professor Olli A. Jänne, Biomedicum Helsinki, University of Helsinki Professor Olli Silvennoinen, Biocenter Finland

Scientific Advisory Board (SAB) of FIMM

The Board of FIMM appoints to the Scientific Advisory Board (SAB) a minimum of six and a maximum of ten internationally recognised experts in the Institute’s fields of research and technological activities. The SAB assess the Institute’s activities and quality of research and provides the Board with recommendations on these matters. The SAB has visited FIMM in 2010 and 2011. In May 2013, a comprehensive 5-year evaluation of the entire institute will be conducted.

Chair: Professor Kai Simons, Max-Planck-Institute of Molecular Cell Biology and Genetics, Germany

Members:

Professor Cornelia van Duijn, Erasmus University Medical School, the Netherlands Professor Carl-Henrik Heldin, Ludwig Institute for Cancer Research, Uppsala University, Sweden Professor Eric S. Lander, The Broad Institute of MIT and Harvard, USA Professor Edison Liu, The Jackson Laboratory, USA Professor Nadia Rosenthal, EMBL Australia Partnership Laboratory, Australia

54 • FIMM Examples of On-going Projects

EU’s 7th Framework Programme, Research Projects

BBMRI-LPC (2013–2017)

BBMRI-LPC (European Biobanking and Biomolecular Research Infrastructure-Large Prospective Cohorts) is a four-year project started in February 2013 funded through the European Integrated Infrastructure Initiative (I3). The project aims to enable academic and industrial scientists to improve our understanding of human biology through enhancing access by academic and industry scientists to the largest European ‘biobanks’, as well as reinforcing biobanking infrastructure and technologies. BBMRI-LPC has received an 8M € EU-funding starting from 2013. The project, bringing together 30 partners from sixteen European countries and Canada, is co-led by Professor Markus Perola from FIMM and Professor Gert-Jan van Ommen from the Leiden University Medical Centre (NL). It represents the next phase of the successful FP7-funded programme BBMRI (Biobanking and Biomolecular Research Infrastructure, 2007–2011). BBMRI-LPC endeavors to unite the large study sets of the European BBMRI and the International Agency for Research on Cancer (IARC), thereby achieving a biobanking network with a scale of integration that is unique worldwide. BBMRI-LPC is expected to catalyse and facilitate the medical research leading to novel and better medicines and treatments for common and rare diseases. Contact Persons at FIMM: Senior Researcher Markus Perola, Research Professor at THL; Senior Researcher Anu Jalanko, Senior Scientist and Head of Unit at THL. http://www.bbmri-lpc.org/

BioMedBridges BIOMEDBRIDGES (2012—2015) BASE LOGO SIZING 100%

BioMedBridges aims at implementing common solutions for a cluster of ESFRI infrastructures in the field of life sciences. It brings together partners from 21 institutions from nine countries and is led by Professor Janet

Base Blue Values Thornton from EMBL-EBI (European Bioinformatics Institute). It will provide the computational ‘data and R 45 B 196 G 224 HEX 2DBAE0 service’ bridges between the individual biological and medical sciences research infrastructures, clustering them

Light Blue Values R 118 B 193 G 231 together and linking the basic biological research and data to the clinical research and associated data. FIMM HEX 76C1E7 coordinates the use of the case work package on personalised medicine, as well as participates in the work Helvetica Neue Light on data standards and a use case on large scale image datasets. As a sign of a successful collaborative project BioMedBridges 48 pt 60% Black and our active participation, FIMM has also contributed to areas beyond its contractual obligations. Contact LOGO 100% persons at FIMM: Professor Olli Kallioniemi and Dr. Imre Västrik. http://www.biomedbridges.eu/

BIOSHARE-EU (2010—2015) BioMedBridges BioMedBridges BioMedBridges

LOGO 72% LOGO 43% LOGO 25% BioSHaRE-EU (Biobank Standardisation and Harmonisation for Research Excellence in the European Union) is a consortium of leading biobanks and international researchers from all domains of biobanking science. The BioMedBridges overall aim of the project is to build upon tools and methods available to achieve solutions for researchers to use LANDSCAPE VARIATION LOGO 43% SIZING LETTERING 36 pt 60% Black

CLIENT : BIOMEDBRIDGES CONTACT : DEBORAH ALVAREZ PROJECT NR. : 2250 pooled data from different cohort and biobank studies. This is done in order to obtain the very large sample sizes DESCRIPTION : LOGO BIOMEDBRIDGES DOCUMENT : 2250_NAAM DATE : 04-06-12 CONTACT : TON DAMEN needed to investigate current questions in multifactorial diseases, notably on gene-environment interactions. APPROVED : This aim will be achieved through the development of harmonization and standardization tools, implementation of these tools and demonstration of their applicability. The project involves sixteen participating organizations, three of them from Canada. FIMM has played a key role and led two work packages in this project. Contact Persons at FIMM: Professor Samuli Ripatti, Professor Aarno Palotie and Senior Researcher Markus Perola, Research Professor at THL. http://www.bioshare.eu/

ENGAGE (2008—2012)

The aim of ENGAGE (European Network for Genetic and Genomic Epidemiology) was to translate the wealth of data emerging from large-scale research in genetic and genomic epidemiology from European (and other) population cohorts into information relevant to future clinical applications. The concept of ENGAGE was to enable European researchers to identify large numbers of novel susceptibility genes that influence metabolic, behavioural and cardiovascular traits, and to study the interactions between genes and life style factors. The ENGAGE Consortium brought together 24 leading research organizations and two biotechnology and pharmaceutical companies across Europe and in Canada and Australia. The project was led by the world- renowned human geneticist Academician of Science, Professor Leena Peltonen from FIMM, University of Helsinki for its first 26 months, until March 2010. The project co-coordinator, Professor Mark McCarthy from

FIMM • 55 the University of Oxford assumed the leadership as Scientific Coordinator since March 2010. FIMM, University of Helsinki was the EC contractual Coordinator. In addition to its active involvement in ENGAGE scientific activities, FIMM also hosted the Coordination Office in charge of day-to-day consortium management and coordination tasks. During the whole project duration, ENGAGE partners have published close to 200 scientific publications relating to project funded activities, many of these in high profile journals that have attracted wider attention. Contact Persons at FIMM: Professor Jaakko Kaprio, Professor Aarno Palotie and Professor Samuli Ripatti. http:// www.euengage.org/

GEN2PHEN (2008— mid 2013)

GEN2PHEN (Genotype-To-Phenotype Databases: A Holistic Solution). The project aims to unify human and model organism genetic variation databases towards increasingly holistic views into Genotype-To-Phenotype (G2P) data, and to link this system into other biomedical knowledge sources via genome browser functionality. The five-year project (2008— mid 2013) is funded with 12 million euros and has 20 participating institutions from Europe, as well as India and South Africa. Contact Person at FIMM: Senior Researcher Juha Muilu. http://www.gen2phen.org/

SYNSYS (2010—2014)

SynSys (Synaptic Systems: dissecting brain function in health and disease) aims at molecular analysis of synapse function and dynamic modelling. The perspective is to generate a blueprint for the discovery of novel pathways and targets that enable rational strategies to design therapies for human brain disease. There are altogether sixteen participating institutions and the funding is for a four-year period of 2010—2014. Contact Person at FIMM: Professor Aarno Palotie. http://www.synsys.eu/

SYSTEMS MICROSCOPY NETWORK OF EXCELLENCE (2011—2015)

The research network Systems Microscopy Network of Excellence joins seventeen multidisciplinary laboratories located throughout Europe, including two new partners accepted to the consortium in 2012. The joint research plan is supported with 12 million euros during 2011–2015. The aim is to develop systems microscopy into a powerful enabling platform for next-generation systems biology, and to make the tools and strategies created for this purpose available to the wider research community. The advances in automated fluorescence microscopy, cell microarray platforms, highly specific probes, quantitative image analysis of cells and tissues, and data mining provide the technology platform to enable “Systems microscopy” of the living cell(s). Through close collaboration between biologists, physicians and mathematicians, this NoE will create mathematical models of mitosis and cell migration in time and space and test them experimentally. As mitosis and cell migration are highly relevant mechanisms underlying cancer, this NoE also aims to identify novel pathways for translational cancer research. In April 2012, FIMM participated the Annual meeting of the consortia (Klosterhof, Germany), where our recent developments were presented in the Work Package report and poster sessions. The presentations from FIMM included the cell spot microarrays and the translational bioinformatic pipeline, which enables choosing the target genes, derived from cell biological studies, for validation in clinical cancer patient samples. During 2012, FIMM initiated a new collaborative project with Leiden University, a NoE partner. Furthermore, Gabriella Rustici from EMBL-EBI, Hinxton, UK (also participating in the Systems Microscopy NoE) visited FIMM for networking discussions and gave a lecture “Towards a public repository for Systems Microscopy data”. Additional information and different tools for image and data analysis, including a cellular phenotype database, are available for the research community: http://www.systemsmicroscopy.eu/network-excellence. Contact Persons at FIMM: Professor Olli Kallioniemi and Senior Researcher Vilja Pietiäinen.

PREDECT (2011—2016)

PREDECT is an IMI-funded partnership between nine academic, three SME and nine EU pharmaceutical company partners, developing advanced, complex in vitro and in vivo models for breast, prostate and lung cancers. Newly developed organotypic cell cultures, attempting to closely mimic in vivo tumours, will be investigated for their improved potential to validate therapeutic targets, applying molecular pathology and systems biology methods to compare the circuitry of resting and perturbed states. PREDECT has built a Europe-wide biobank of cancer model systems and a web microscopy-based tissue microarray data sharing system as a collaborative platform between academia and industry. FIMM/University of Helsinki is the academic coordinator of the project, which currently consists of around 60 researchers in around 27 laboratories. Contact persons at FIMM: Group Leader Emmy Verschuren (Academic Coordinator of PREDECT), Professor Olli Kallioniemi and Research Director Johan Lundin. http://www.predect.eu/

56 • FIMM ESFRI Projects (European Strategy Forum on Research Infrastructures)

EU-OPENSCREEN PREPARATORY PHASE (2010—2013)

EU-OPENSCREEN (European Infrastructure of Open Screening Platforms for Chemical Biology) integrates high throughput screening platforms, chemical libraries, chemical resources for hit discovery and optimisation, bio- and cheminformatics support, and a database containing screening results, assay protocols, and chemical information. In the current preparatory phase (2010—2013), the network contains 21 partner institutes/ institutions representing fourteen European countries. FIMM is the partner representing Finland in the network. Contact persons at FIMM: Group Leader Krister Wennerberg, Senior Researchers Heidi Virtanen, Gretchen Repasky and Leena Karhinen, and Professor Olli Kallioniemi (www.eu-openscreen.eu).

BIOMEDINFRA: BBMRI, EATRIS, ELIXIR (2010—2013)

Biomedinfra is a Finnish collaborative endeavour to participate in the implementation of European biobanking (BBMRI), bioinformatics (ELIXIR) and translational research (EATRIS) infrastructures. The Biomedinfra consortium brings together the National Institute for Health and Welfare (THL), CSC - IT Center for Science Ltd and FIMM/University of Helsinki. The Ministry of Education and Culture via the Academy of Finland has funded the build-up of the respective national infrastructures. At FIMM, the funding has been used to establish the Meilahti Integrated Biobanking Infrastructure, to develop new imaging technologies, as well as to strengthen FIMM Technology Centre’s molecular profiling and bioinformatics capacities relevant to translational research. At the European level, FIMM director Olli Kallioniemi chairs the EATRIS Biomarkers Product Group - one of the five technology areas in EATRIS. By the end of 2012, ten countries had pledged support to setting up EATRIS as European Research Infrastructure Consortium (ERIC) legal entity and EATRIS had successfully completed the first stage of the two-stage application process. EATRIS is expected to be formally established during the first half of 2013. Contact persons at FIMM: Professor Olli Kallioniemi and Dr. Imre Västrik

Marie Curie Actions

PRO-NEST (2009—2013)

PRO-NEST (Prostate Research Organizations-Network of Early Stage Training) is a Marie Curie Initial Training Network that offers training on all aspects of prostate cancer research, ranging from the molecular basis of this disease to the translation of biomarkers into the clinic, to 24 PhD students and starting post-docs. The ultimate scientific aim of PRO-NEST is to understand the molecular basis of prostate cancer to address prevention, and to provide novel biomarkers and therapeutic targets for monitoring and treatment of this major European health problem. PRO-NEST has started in 2009 for a period of four years until 2013. Contact persons at FIMM: Senior Researchers Gretchen Repasky and Päivi Östling and Professor Olli Kallioniemi. www.pro-nest.org

SYSTUMS (2010—2014)

SYSTUMS (Systems Biology Approaches to Novel Tumour Suppressors) is a project funded by a Marie Curie International Reintegration Grant aiming to study protein networks and molecular functions regulated by the candidate tumour suppressor protein EphA3. This action funds individual projects presented by experienced researchers returning to Europe after having worked in a non-associated third country for at least three years, to assist in reintegration and promote transfer of knowledge into EU Member States or Associated Countries. Grantee at FIMM: Group Leader Emmy Verschuren, for reintegration period 2010—2014.

FIMM • 57 European Regional Development Fund

LifeMarkers – Promoting health by biomarker-based new diagnostics and services (2011–2013)

The LifeMarkers project (“Elämän merkit” in Finnish) is coordinated by Turku Science Park Ltd. Other participants in the project are (1) Culminatum Innovation Ltd, Helsinki, (2) Institute for Molecular Medicine Finland (FIMM), University of Helsinki, (3) Institute of Biomedicine, University of Turku, (4) Turku University Hospital, Hospital District of South West Finland and (5) Technical Research Centre of Finland (VTT). The project is funded by European Regional Development Fund (ERDF) and by the participants. The aim of the project is to develop biomarker-based new diagnostics tools and services for acute myeloid leukemia, ovarian cancer and endometriosis, as well as to promote the high quality academic research in the area of biomarker discovery in Southern Finland. FIMM is developing a process for using personalised biomarkers for measuring treatment efficacy and early detection of relapse in leukaemia patients. During 2012, FIMM developed a “Fast Track” sequencing and bioinformatics analysis workflow for personalised medicine samples. Contact persons at FIMM: Professor Olli Kallioniemi and Dr. Imre Västrik.

National Infrastructures

FIMM research groups and the Technology Centre were involved in six Biocenter Finland infrastructure networks: Bioinformatics (Imre Västrik); Genome-Wide Methods (Janna Saarela); Translational technologies: Drug Discovery and Chemical Biology (Olli Kallioniemi and Krister Wennerberg) and Biobank (Johan Lundin); Metabolomics (Vidya Vegalapudi); Emerging technologies: LentiGEMM (Emmy Verschuren and Sergey Kuznetsov).

DDBC

The Biocenter Finland Drug Discovery and Chemical Biology (DDCB) platform aims to coordinate and integrate the significant infrastructure and expertise in the areas of drug discovery and chemical biology that exist in Finland and make it available to the scientific community. DDCB is coordinated from FIMM and the other partner organizations are Biocenter Kuopio (UEF), Centre for Drug Research (UH), Biocity Turku (ÅA), CSC-IT Center for Science and VTT. The expertise within the network include drug discovery & chemical biology process guidance and advice, assay development, HTS, HCS, virtual screening, molecular modeling, chemoinformatics, follow-up assays, in silico and in vitro ADMET, and connections to organic/medicinal chemistry. Contact persons at FIMM: Group Leader Krister Wennerberg and Senior Researchers Heidi Virtanen and Leena Karhinen.

58 • FIMM A year at FIMM

A typical year at FIMM encompasses a number of wide ranging promotional and social activities.

February

During the year when Helsinki was the World Design Capital the aim of the University of Helsinki was to take top-level research to the public, to ignite lively debate on various topics. The Think Corner, Tiedekulma, at Aleksanterinkatu 7 was opened in February. The Think Corner was a meeting place for the university community and the public, turning science into an approachable experience. The opening theme of the Think Corner was Health and Well-being, with FIMM taking active involvement through many researchers giving lectures to the public on, e.g. biobanking and personalised medicine.

March

On 20 March, the hallways and laboratories of FIMM were full of young, energetic visitors, when FIMM took part in the Meilahti Campus Day. FIMM was one of the most popular places to visit during the day, with nearly 150 high school students being given the opportunity to see our researchers at work. The multitouch webmicroscope was an experience to remember for many. Furthermore, several individual groups from schools around Southern Finland visited FIMM during the year. These visits have raised awareness of the institute and also given the opportunity for young people to get information on research and a researcher’s career.

The spring was the time of active preparation of the FIMM Target Programme for the next four years (2013— 2016). A Future Day was organised on 2 March as a kick-off seminar to start discussion with FIMM staff and the preparation of the Programme. The aim of the seminar was to involve FIMM staff in the discussion from the very beginning. Staff provided vital feed-back to the institute on key initiatives within six broad thematic areas that were identified for further planning, e.g. FIMM’s profile, visibility and outreach; researcher training and careers; translation and innovation. The preparation of the Target Programme was continued with a Strategy Seminar to the Board of FIMM in June.

FIMM • 59 May

FiDiPro Professor Jonathan Knowles has taken an active role in promoting personalised medicine, and advocating Finland to become a world-leader in this field. Professor Knowles, as well as the Director and Research Directors of FIMM, have participated in a number of stakeholder events and have given several talks, including interviews to national and international magazines. The Chancellor of the University of Helsinki, Professor Ilkka Niiniluoto visited FIMM on 28 May 2012. The national “grand challenge” on personalised medicine was discussed. Together with the Chancellor, FIMM instigated preparations for a national high-level discussion event on personalised medicine. This successful event was held in February 2013 in Helsinki (Finlandia Hall) and included experts representing preventive health care, clinical medicine and industry, as well as decision and policy makers from Ministries, research funding and health care organizations.

The FIMM Scientific Retreat was arranged on 29–30 May in Siikaranta. This annual event was organised for the third time, and is becoming a key event for developing FIMM’s scientific and organizational identity. Importantly, the location offered a possibility to concentrate on creating and strengthening new collaborations within the institute. 146 staff members enjoyed two days of interesting lectures, productive workshops and outdoor activities. This time the programme concentrated on introducing the numerous infrastructure projects involving FIMM.

60 • FIMM June

FIMM has its own Entertainment Committee for the organisation of social events, designed to increase cross institute communication. For this year, a Spring Break, half a day-event with games, sausages and drinks in Seurasaari was organized. This event was held on 1 June and approximately 50 people enjoyed the various team activities. The Entertainment Committee in 2012 included: Henrikki Almusa, Yuexi Gu, Marika Karjalainen, Anna Kossila, Ida Lindenschmidt, Mamun Muntasir, Aino Palva, Annabrita Schoonenberg, Sanna Uusivirta, Heidi Virtanen.

Olli Kallioniemi and Aarno Palotie gave a talk on 12 June 2012 in a seminar organised by TUTKAS (Association of the researchers and Members of Parliament). The seminar was entitled ’Genomitieto kertoo — Mistä tulemme, mihin menemme’. They also participated by invitation to expert consultations of the Parliament of Finland concerning the proposed Biobank Law expected to enter into force in 2013.

August

FIMM had many visitors in 2012, e.g. from national and international research funding organisations, other universities, research institutions and organisations (including Broad Institute, Innovative Medicines Initiative IMI, Sitra, Karolinska Institutet/Biobank). In August eight members of the Finnish Parliament, Rector Thomas Wilhelmsson and all four Vice-Rectors of the University of Helsinki visited. The visit was hosted by the Rector and the programme concentrated on the medical research performed at the Meilahti campus. FIMM infrastructure and research projects were introduced.

FIMM • 61 September

In September, FIMM strengthened its link to the Nordic EMBL Partnership for Molecular Medicine. The Spanish EMBL Partnership, Centre for Genomic Regulation (CRG) in Barcelona, hosted a scientific conference on the topic of “Perspectives in Translational Medicine”. There were approximately 120 participants, including representatives from the EMBL. Thirty FIMM participants presented research highlights at this conference, either by giving a talk or presenting a poster. The Nordic nodes will continue to strengthen the collaboration at all levels in the forthcoming years.

November

Twenty-two science journalists were given a taste of personalised medicine research at FIMM on 20 November. Olli Kallioniemi, Jonathan Knowles, Aarno Palotie and Samuli Ripatti gave short presentations and thereafter the visitors toured some of the core facility and biobanking laboratories. Many of the reporters undertook an experimental gene test to predict their cardiovascular risks. The media professionals enjoyed the visit and have written about it in several stories.

62 • FIMM FIMM’s Entertainment Committee arranged the annual Christmas party, FIMM pikkujoulu, for all personnel on 16 of November. After a nice dinner at restaurant Ranta Aura, partygoers enjoyed a great karaoke show.

The third annual FIMM poster session was arranged on 20 November. The session was organized by senior researchers Leena Karhinen and Gretchen Repasky and nearly 40 posters were presented. Presenters included PhD students, postdoctoral and senior researchers, and all aspects of FIMM activities were well represented. This annual event plays an important role in increasing knowledge, building team spirit and adding collaboration within the institute.

January

Olli Kallioniemi’s Inauguration Lecture “Personalised Medicine 2020” took place in January 2013. The lecture was a great success with nearly 300 people attending it.

FIMM • 63 FIMM in Figures

Financial Report

4 % 7 % 22 %

Basic funding

Strategic funding 2 %

Competitive external funding

Service revenue (external)

Service revenue (internal) 65 %

Figure 1. Total funding of FIMM in 2012 (15.5 M€) divided based on the source of income. The basic funding refers to the support from the University of Helsinki. External funding refers to competitive research and infrastructure funding.

10 % 11 % 0,1 %

18 % Biocenter Finland Foundations

Academy of Finland EU (including ESRFI)

34 % TEKES Other international funding

11 % Other public funding Service revenue (external) (including THL, HUS, City of Helsinki) 8 % 8 %

Figure 2. Distribution of FIMM external funding 2012 (11.2 M€) according to the source of income.

16 %

Personnel costs 1 % Facilities

10 % Consumables 53 % Equipment

15 % Depreciation

Services and other costs 5 %

Figure 3. FIMM expenditure (14.5 M€) 2012.

64 • FIMM Personnel statistics

200 120 180 2008 160 100 140 2009 80 120 100 60 2010 80 40 60 2011 40 20 20 2012 0 0 2007 2008 2009 2010 2011 2012 2013 Research Support personnel Administrative IT personnel personnel for research personnel

Figure 4. Total number of FIMM employees 2007–2012, an estimate for 2013. Figure 5. Number of FIMM personnel 2008–2012 according to the type of employment.

Research personnel

Support personnel for research 42 Administrative personnel 112 IT personnel

Figure 6. Number of FIMM personnel in 2012 according to the type of employment.

10 % 3 % 4th level (Professors and Research 4 % 19 % Directors)

3rd level (Research Coordinators, Senior Researchers

2nd level (Post-Doctoral Researchers)

24 % 11 % 1st level (Project Researchers, Doctoral Students, Research Assistants)

Support personnel for teaching and research

Administrative personnel 29 % IT personnel

Figure 7. Distribution of FIMM personnel by category of employment.

FIMM • 65 Finland 141

Russia 9

Japan 1 Canada 1 China 3 Sweden 2

Great Britain 4 Denmark 1 Taiwan 1

USA 5 Estonia 1 Nepal 3 Pakistan 1 Mexico 1 Netherlands 4 Germany 2 Poland 1 Vietnam 1

France 1 India 10

Trinidad and Tobago 1 Slovenia 1 Bangladesh 2

Portugal 1 Macedonia 1 Italy 2 Spain 3

Uganda 1

Figure 8. Nationalities represented among FIMM personnel (during the year 2012)

Size and structure of FIMM personnel on 31 December 2012 (number of personnel 184, 24 nationalities): • FIMM personnel: 56 % are women and 44 % men. The average age is 37.1 years. 29 % of the whole personnel are international. • Research personnel: 55 % are women and 45 % men. The average age is 35.7 years. 37 % of the research personnel are international. • Doctoral students: 52 % are women and 48 % men. The average age is 29.1 years. 52 % of the doctoral students are international.

66 • FIMM Personnel including researchers and students with grants and members of the FIMM National Network for Molecular Medicine

Research groups Ville Ojansivu Sari Bombino Minttu Sauramo Antti Suutala Myles Byrne Kaisa Silander Riku Turkki Bhargavi Carasala Tuuli Sistonen Tero Aittokallio Margarita Walliander Kati Donner Kyosti Sutinen Himanshu Chheda Henrik Edgren Minna Suvela Petteri Hintsanen Aarno Palotie Sirkka Ekstrom Arja Terola Teemu Daniel Laajala Eija Hamalainen Samuli Eldfors Tiina Vesterinen Antonio Neme Carita Jussila Pekka Ellonen Anne Vikman Agnieszka Szwajda Elli Kempas Sari Hannula Regis Wong Jing Tang Sari Kivikko Tiina Hannunen Bhagwan Yadav Leena Leikas Jani Heikkinen FIMM Administration and Tao Xu Tiia Luukkonen Vasudev Kantae Coordinators Mikko Muona Mari Kaunisto Olli Kallioniemi William Hennah Anne Nyrhinen Mervi Kinnunen Riitta Alatalo Alfredo Ortega Alonso Mari Rossi Annika Korvenpää Heidi Arling Tripepi Olli Pietiläinen Anna Kossila Mika Frederiksen Denis Kainov Maija Wessman Evgeny Kulesskiy Sanni Hypponen Maria Anastasina Anne Vikman Suvi Kyttänen Mari Kaunisto Oxana Denisova Karoliina Laamanen Sari Kivikko Laura Kakkola Juni Palmgren Sonja Lagström Riitta Koskinen Minttu Kaloinen Alfredo Ortega-Alonso Päivi Lahermo Marja Medina Johanna Lampe Ola Spjuth Anna Lehto Reetta Niemela Anne Leinonen Kari Pitkanen Olli Kallioniemi Maija Lepistö Gretchen Repasky Anna Aakula Samuli Ripatti Ida Lindenschmidt Susanna Rosas Mariliina Arjama Himanshu Chheda Jesus Maria Lopez Marti Huei-yi Shen Sami Blom Johannes Kettunen Pirkko Mattila Birgit Simell Oscar Brück Pirkka-Pekka Laurila Ruusu-Maaria Merivirta Virve Tiusanen Dimitri Bychkov Matti Pirinen Timo Miettinen Imre Västrik Henrik Edgren Pietari Ripatti Juha Muilu Ella Westerlund Akira Hirasawa Mari Rossi Aino Palva Susanne Hultsch Antti-Pekka Sarin Teemu Perheentupa EMBL students in rotation Taija af Hällström Huei-Yi Shen Vilja Pietiainen Meri Kaustio Sara Kangaspeska Ida Surakka Anne Polvi Alok Jaiswal Disha Malani Emmi Tikkanen Swapnil Potdar John Patrick Mpindi Taru Tukiainen Jani Saarela FIMM Clinical Astrid Murumägi Peter Wurtz Janna Saarela Collaborators Petra Mäki-Teeri Tomi Simonen Tuomas Mirtti Kalle Ojala Janna Saarela Jouko Siro Kirsi Pietiläinen Teijo Pellinen Henrikki Almusa Kyosti Sutinen Jakob Stenman Vilja Pietiäinen Virpi Leppä Oskari Torppa Khalid Saeed Annu Näkki Kari Tuomainen Members of the FIMM Jenni Säilä Anna-Maija Sulonen Hannu Turunen National Network for Poojitha Kota Venkata Luca Trotta Laura Turunen Molecular Medicine Katja Välimäki Carina von Schantz-Fant Lauri A. Aaltonen Maija Wolf Emmy Verschuren Syed Arshi Uz Zaman Kari Alitalo Paivi Östling Jenni Lahtela Heidi Virtanen Akseli Hemminki Rita Matos Imre Västrik Iiris Hovatta Jonathan Knowles Ashwini Nagaraj Vidya Velagapudi Elina Ikonen Samuli Eldfors Dat Nguyen Krister Wennerberg Sirpa Jalkanen Caroline Heckman Katja Närhi Anu Yliperttula Heikki Joensuu Riikka Karjalainen Elina Parri Jean-Christophe Yorke Jaakko Kaprio Jarno Kivioja Nitai Peled Paivi Östling Heli Nevanlinna Ashwini Kumar Annabrita Schoonenberg Matej Orešič Heikki Kuusanmaki Biobank Infrastructure, in- Taina Pihlajaniemi Muntasir Mamun Majumder Krister Wennerberg cluding THL personnel: Jussi Taipale Alun Parsons Arjan van Adrichem Niina Eklund Willem de Vos Leena Karhinen Taija af Hällström Anu Wartiovaara Sergey Kuznetsov Sawan Kumar Jha Askar Ibragimov Jukka Westermarck Daria Bulanova Muntasir Mamun Majumder Anu Jalanko Yuexi Gu Tea Pemovska Siv Knaappila Collaborative Positions Sharif Iqbal Gretchen Repasky Aija Kyttälä Tero Hiekkalinna Sonja Koopal Agnieszka Szwajda Päivi Laiho Jenni Hällfors Pauliina Munne Sini Lähteenmäki Anni Joensuu Manuela Tumiati Elisabeth Widén Tuomas Mirtti Tarja Laitinen Diana Cousminer Juha Muilu Hannele Mattson Johan Lundin Jaakko Leinonen Elina Mäkinen Marja-Liisa Nuotio Anne Grote Anne Nyberg Markus Perola Juho Konsti FIMM Technology Kimmo Pitkanen Antti Poso Tiina Lehtimäki Centre, including Maija Puhka Elina Salmela Nina Linder infrastructure projects Seija Puomilahti Mikael Lundin Henrikki Almusa Reija Randen-Brady

FIMM • 67 Publications 2012

Publications by FIMM researchers 8. Effect of a common variant of the PCSK2 gene on reduced insulin secretion. / Jonsson, A.; Isomaa, B.; Tuomi, T.; Eriksson, J. G.; Groop, L.; Lyssenko, V. In: Diabetologia, Vol. 55, No. 12, 01.12.2012, p. 3245-3251. 1. Chemical Biology Drug Sensitivity Screen Identifies Sunitinib as Synergistic Agent with Disulfiram in 9. A Genome-Wide Association Study of Monozygotic Prostate Cancer Cells. / Ketola, Kirsi; Kallioniemi, Olli; Twin-Pairs Suggests a Locus Related to Variability Iljin, Kristiina. In: PLoS One, Vol. 7, No. 12, 12.12.2012, of Serum High-Density Lipoprotein Cholesterol. p. Article Number: e51470. / Surakka, Ida; Whitfield, John B.; Perola, Markus; Visscher, Peter M.; Montgomery, Grant W.; Falchi, Mario; 2. High-throughput RNAi screening for novel Willemsen, Gonneke; de Geus, Eco J. C.; Magnusson, modulators of vimentin expression identifies Patrik K. E.; Christensen, Kaare; Sorensen, Thorkild I. A.; MTHFD2 as a regulator of breast cancer cell Pietiläinen, Kirsi Hannele; Rantanen, Taina; Silander, migration and invasion. / Lehtinen, Laura; Ketola, Kaisa; Widen, Elisabeth; Muilu, Juha; Rahman, Iffat; Kirsi; Mäkelä, Rami; Mpindi, John Patrick; Viitala, Miro; Liljedahl, Ulrika; Syvanen, Ann-Christine; Palotie, Aarno; Kallioniemi, Olli; Iljin, Kristiina. In: Oncotarget, Vol. 3, Kaprio, Jaakko; Kyvik, Kirsten O.; Pedersen, Nancy L.; No. 0, 09.12.2012, p. 1-10. Boomsma, Dorret I.; Spector, Tim; Martin, Nicholas G.; Ripatti, Samuli; Palotie, Leena; GenomEUtwin Project. 3. Lack of MMP-9 expression is a marker for poor In: Twin Research and Human Genetics, Vol. 15, No. 6, prognosis in Dukes’ B colorectal cancer. / Selja, 12.2012, p. 691-699. Koskensalo; Hagström, Jaana Kristiina; Linder, Nina; 10. Eturauhassyövän yksilöllinen hoitovalinta - apuna Lundin, Mikael Edvard; Sorsa, Timo; Louhimo, Johanna; molekyylipatologiset merkkiaineet ja biopankki. / Haglund, Caj. In: BMC Clinical Pathology, Vol. 12, No. 24, Mirtti, Tuomas; Rannikko, Antti Sakari. In: Duodecim, 07.12.2012. Vol. 128, No. 24, 12.2012, p. 2497-2499.

4. A Potential Novel Spontaneous Preterm Birth Gene, 11. Lamstatin - a novel inhibitor of lymphangiogenesis AR, Identified by Linkage and Association Analysis derived from collagen IV. / Weckmann, Markus; Moir, of X Chromosomal Markers. / Karjalainen, Minna K.; Lyn Margaret; Heckman, Caroline Akemi; Oliver, Brian Huusko, Johanna M.; Ulvila, Johanna; Sotkasiira, Jenni; Gregory; Burgess, Janette Kay. In: Journal of Cellular and Luukkonen, Aino; Teramo, Kari; Plunkett, Jevon; Anttila, Molecular Medicine, Vol. 16, No. 12, 12.2012, p. 3062- Verneri; Palotie, Aarno; Haataja, Ritva; Muglia, Louis J.; 3073. Hallman, Mikko. In: PLoS One, Vol. 7, No. 12, 05.12.2012, p. Article Number: e51378. 12. A Comparison of the Whole Genome Approach of MeDIP-Seq to the Targeted Approach of the Infinium 5. Systemic Analysis of Gene Expression Profiles HumanMethylation450 BeadChip (R) for Methylome Identifies ErbB3 as a Potential Drug Target in Profiling. / Clark, Christine; Palta, Priit; Joyce, Pediatric Alveolar Rhabdomyosarcoma. / Nordberg, Christopher J.; Scott, Carol; Grundberg, Elin; Deloukas, Janne; Mpindi, John Patrick; Iljin, Kristiina; Pulliainen, Panos; Palotie, Aarno; Coffey, Alison J. In: PLoS One, Vol. Arto Tapio; Kallajoki, Markku; Kallioniemi, Olli; Elenius, 7, No. 11, 29.11.2012, p. Article Number: e50233 . Klaus; Elenius, Varpu. In: PLoS One, Vol. 7, No. 12, 05.12.2012, p. Article Number: e50819. 13. Association of LIN28B with Adult Adiposity-Related Traits in Females. / Leinonen, Jaakko T.; Surakka, Ida; 6. A Single-Nucleotide Substitution Mutator Havulinna, Aki S.; Kettunen, Johannes; Luoto, Riitta; Phenotype Revealed by Exome Sequencing of Salomaa, Veikko; Widen, Elisabeth. In: PLoS One, Vol. 7, Human Colon Adenomas. / Nikolaev, Sergey I.; No. 11, 13.11.2012, p. Article Number: e48785. Sotiriou, Sotirios K.; Pateras, Ioannis S.; Santoni, Federico; Sougioultzis, Stavros; Edgren, Henrik; Almusa, 14. Branched-Chain and Aromatic Amino Acids Are Henrikki; Robyr, Daniel; Guipponi, Michel; Saarela, Predictors of Insulin Resistance in Young Adults. Janna; Gorgoulis, Vassilis G.; Antonarakis, Stylianos E.; / Wurtz, P; Soininen, P; Kangas, A J; Ronnemaa, T; Halazonetis, Thanos D. In: Cancer Research, Vol. 72, No. Lehtimäki, T; Kahonen, M; Viikari, J S; Raitakari, O T; Ala- 23, 01.12.2012, p. 6279-6289. Korpela, M. In: Diabetes Care, 01.11.2012.

7. Citation Classic: Introducing Tissue Microarrays to 15. Genome-wide meta-analysis of common variant Molecular Pathology. / Kallioniemi, Olli; Kononen, Juha; differences between men and women. / Wellcome Sauter, Guido. In: Clinical Chemistry (Washington, DC), Trust Case Control. In: Human Molecular Genetics, Vol. Vol. 58, No. 12, 01.12.2012, p. 1717-1718. 21, No. 21, 01.11.2012, p. 4805-4815.

68 • FIMM 16. Toward a roadmap in global biobanking for health. A.; Consortium, Grp. In: Biological Psychiatry, Vol. 72, No. / Harris, Jennifer R.; Burton, Paul; Knoppers, Bartha 8, 15.10.2012, p. 645-650. Maria; Lindpaintner, Klaus; Bledsoe, Marianna; Brookes, Anthony J.; Budin-Ljosne, Isabelle; Chisholm, Rex; Cox, 21. Obatoclax, Saliphenylhalamide, and Gemcitabine David; Deschenes, Mylene; Fortier, Isabel; Hainaut, Inhibit Influenza A Virus Infection. / Denisova, Oxana Pierre; Hewitt, Robert; Kaye, Jane; Litton, Jan-Eric; V.; Kakkola, Laura; Feng, Lin; Stenman, Jakob; Nagaraj, Metspalu, Andres; Ollier, Bill; Palmer, Lyle J.; Palotie, Ashwini; Lampe, Johanna; Yadav, Bhagwan; Aittokallio, Aarno; Pasterk, Markus; Perola, Markus; Riegman, Peter Tero; Kaukinen, Pasi; Ahola, Tero; Kuivanen, Suvi; H. J.; van Ommen, Gert-Jan; Yuille, Martin; Zatloukal, Vapalahti, Olli; Kantele, Anu; Tynell, Janne; Julkunen, Kurt. In: European Journal of Human Genetics, Vol. 20, Ilkka; Kallio-Kokko, Hannimari; Paavilainen, Henrik; No. 11, 01.11.2012, p. 1105-1111. Hukkanen, Veijo; Elliott, Richard M.; De Brabander, Jef K.; Saelens, Xavier; Kainov, Denis E. In: Journal of Biological 17. Mortality Rate Increases Steeply With Chemistry, Vol. 287, No. 42, 12.10.2012, p. 35324-35332. Nonadherence to Statin Therapy in Patients With Acute Coronary Syndrome. / Allonen, Jaakko; 22. FTO genotype is associated with phenotypic Nieminen, Markku S.; Lokki, Maisa; Parkkonen, variability of body mass index. / Yang, Jian; Loos, Ruth Olavi; Vaara, Satu; Perola, Markus; Hiekkalinna, Tero; J. F.; Powell, Joseph E.; Medland, Sarah E.; Speliotes, Strandberg, Timo E.; Sinisalo, Juha. In: Clinical Cardiology Elizabeth K.; Chasman, Daniel I.; Rose, Lynda M.; (Hoboken), Vol. 35, No. 11, 11.2012, p. E22-E27. Thorleifsson, Gudmar; Steinthorsdottir, Valgerdur; Maegi, Reedik; Waite, Lindsay; Smith, Albert Vernon; 18. Reanalysis of RNA-Sequencing Data Reveals Several Yerges-Armstrong, Laura M.; Monda, Keri L.; Hadley, Additional Fusion Genes with Multiple Isoforms. / David; Mahajan, Anubha; Li, Guo; Kapur, Karen; Vitart, Kangaspeska, Sara; Hultsch, Susanne; Edgren, Henrik; Veronique; Huffman, Jennifer E.; Wang, Sophie R.; Nicorici, Daniel; Murumagi, Astrid; Kallioniemi, Olli. n: Palmer, Cameron; Esko, Toenu; Fischer, Krista; Zhao, PLoS One, Vol. 7, No. 10, 31.10.2012, p. Article Number: Jing Hua; Demirkan, Ayse; Isaacs, Aaron; Feitosa, Mary e48745. F.; Luan, Jian’an; Heard-Costa, Nancy L.; White, Charles; 19. Proteomic, genomic and translational approaches Jackson, Anne U.; Preuss, Michael; Ziegler, Andreas; identify CRMP1 for a role in schizophrenia and Eriksson, Joel; Kutalik, Zoltan; Frau, Francesca; Nolte, Ilja its underlying traits. / Bader, Verian; Tomppo, Liisa; M.; Van Vliet-Ostaptchouk, Jana V.; Hottenga, Jouke- Trossbach, Svenja V.; Bradshaw, Nicholas J.; Prikulis, Jan; Jacobs, Kevin B.; Verweij, Niek; Goel, Anuj; Medina- Ingrid; Leliveld, S. Rutger; Lin, Chi-Ying; Ishizuka, Koko; Gomez, Carolina; Estrada, Karol; Bragg-Gresham, Jennifer Sawa, Akira; Ramos, Adriana; Rosa, Isaac; Garcia, Angel; Lynn; Sanna, Serena; Sidore, Carlo; Tyrer, Jonathan; Requena, Jesus R.; Hipolito, Maria; Rai, Narayan; Nwulia, Teumer, Alexander; Prokopenko, Inga; Mangino, Evaristus; Henning, Uwe; Ferrea, Stefano; Luckhaus, Massimo; Lindgren, Cecilia M.; Assimes, Themistocles L.; Christian; Ekelund, Jesper; Veijola, Juha; Jarvelin, Marjo- Shuldiner, Alan R.; Hui, Jennie; Beilby, John P.; McArdle, Riitta; Hennah, William; Korth, Carsten. In: Human Wendy L.; Hall, Per; Haritunians, Talin; Zgaga, Lina; Molecular Genetics, Vol. 21, No. 20, 15.10.2012, p. 4406- Kolcic, Ivana; Polasek, Ozren; Zemunik, Tatijana; Oostra, 4418. Ben A.; Junttila, M. Juhani; Groenberg, Henrik; Schreiber, Stefan; Peters, Annette; Hicks, Andrew A.; Stephens, 20. Replication Study and Meta-Analysis in European Jonathan; Foad, Nicola S.; Laitinen, Jaana; Pouta, Anneli; Samples Supports Association of the 3p21.1 Locus Kaakinen, Marika; Willemsen, Gonneke; Vink, Jacqueline with Bipolar Disorder. / Vassos, Evangelos; Steinberg, M.; Wild, Sarah H.; Navis, Gerjan; Asselbergs, Folkert Stacy; Cichon, Sven; Breen, Gerome; Sigurdsson, W.; Homuth, Georg; John, Ulrich; Iribarren, Carlos; Engilbert; Andreassen, Ole A.; Djurovic, Srdjan; Morken, Harris, Tamara; Launer, Lenore; Gudnason, Vilmundur; Gunnar; Grigoroiu-Serbanescu, Maria; Diaconu, Carmen O’Connell, Jeffrey R.; Boerwinkle, Eric; Cadby, Gemma; C.; Czerski, Piotr M.; Hauser, Joanna; Babadjanova, Gulja; Palmer, Lyle J.; James, Alan L.; Musk, Arthur W.; Ingelsson, Abramova, Lilia I.; Muehleisen, Thomas W.; Noethen, Erik; Psaty, Bruce M.; Beckmann, Jacques S.; Waeber, Markus M.; Rietschel, Marcella; McGuffin, Peter; St Clair, Gerard; Vollenweider, Peter; Hayward, Caroline; Wright, David; Gustafsson, Omar; Melle, Ingrid; Pietiläinen, Olli; Alan F.; Rudan, Igor; Groop, Leif C.; Metspalu, Andres; Ruggeri, Mirella; Tosato, Sarah; Werge, Thomas; Ophoff, Khaw, Kay Tee; van Duijn, Cornelia M.; Borecki, Ingrid Roel A.; Rujescu, Dan; Borglum, Anders D.; Mors, Ole; B.; Province, Michael A.; Wareham, Nicholas J.; Tardif, Mortensen, Preben B.; Demontis, Ditte; Hollegaard, Jean-Claude; Huikuri, Heikki V.; Cupples, L. Adrienne; Mads V.; van Winkel, Ruud; Kenis, Gunter; De Hert, Atwood, Larry D.; Fox, Caroline S.; Boehnke, Michael; Marc; Rethelyi, Janos M.; Bitter, Istvan; Rubino, I. Alex; Collins, Francis S.; Mohlke, Karen L.; Erdmann, Jeanette; Golimbet, Vera; Kiemeney, Lambertus A.; van den Berg, Schunkert, Heribert; Hengstenberg, Christian; Stark, Leonard H.; Franke, Barbara; Jonsson, Erik G.; Farmer, Klaus; Lorentzon, Mattias; Ohlsson, Claes; Cusi, Anne; Stefansson, Hreinn; Stefansson, Kari; Collier, David Daniele; Staessen, Jan A.; Van der Klauw, Melanie M.;

FIMM • 69 Pramstaller, Peter P.; Kathiresan, Sekar; Jolley, Jennifer 26. Effect of short-term carbohydrate overfeeding and D.; Ripatti, Samuli; Jarvelin, Marjo-Riitta; de Geus, Eco long-term weight loss on liver fat in overweight J. C.; Boomsma, Dorret I.; Penninx, Brenda; Wilson, humans. / Sevastianova, Ksenia; Pereira Delgado e James F.; Campbell, Harry; Chanock, Stephen J.; van der Santos, Alexandre; Kotronen, Anna; Hakkarainen, Antti; Harst, Pim; Hamsten, Anders; Watkins, Hugh; Hofman, Makkonen, Janne; Silander, Kaisa; Peltonen, Markku Albert; Witteman, Jacqueline C.; Zillikens, M. Carola; Kalevi; Romeo, Stefano; Lundbom, Jesper; Lundbom, Uitterlinden, Andre G.; Rivadeneira, Fernando; Zillikens, Nina; Olkkonen, Vesa M.; Gylling, Helena; Fielding, M. Carola; Kiemeney, Lambertus A.; Vermeulen, Sita H.; Barbara A.; Rissanen, Aila; Yki-Jarvinen, Hannele. In: Abecasis, Goncalo R.; Schlessinger, David; Schipf, Sabine; American Journal of Clinical Nutrition, Vol. 96, No. 4, Stumvoll, Michael; Toenjes, Anke; Spector, Tim D.; North, 01.10.2012, p. 727-734. Kari E.; Lettre, Guillaume; McCarthy, Mark I.; Berndt, Sonja I.; Heath, Andrew C.; Madden, Pamela A. F.; Nyholt, 27. Maintenance of genetic variation in human Dale R.; Montgomery, Grant W.; Martin, Nicholas G.; personality: Testing evolutionary models by McKnight, Barbara; Strachan, David P.; Hill, William G.; estimating heritability due to common causal Snieder, Harold; Ridker, Paul M.; Thorsteinsdottir, Unnur; variants and investigating the effect of distant Stefansson, Kari; Frayling, Timothy M.; Hirschhorn, Joel inbreeding. / Verweij, Karin J. H.; Yang, Jian; Lahti, Jari; N.; Goddard, Michael E.; Visscher, Peter M. In: Nature, Veijola, Juha; Hintsanen, Mirka; Pulkki-Raback, Laura; Vol. 490, No. 7419, 11.10.2012, p. 267-U178. Heinonen, Kati; Pouta, Anneli; Pesonen, Anu-Katriina; Widen, Elisabeth; Taanila, Anja; Isohanni, Matti; 23. VarioML framework for comprehensive variation Miettunen, Jouko; Palotie, Aarno; Penke, Lars; Service, data representation and exchange. / Byrne, Myles; Susan K.; Heath, Andrew C.; Montgomery, Grant W.; Fokkema, Ivo F. A. C.; Lancaster, Owen; Adamusiak, Raitakari, Olli; Kahonen, Mika; Viikari, Jorma; Räikkönen, Tomasz; Ahonen-Bishopp, Anni; Atlan, David; Beroud, Katri; Eriksson, Johan G.; Keltikangas-Jarvinen, Liisa; Christophe; Cornell, Michael; Dalgleish, Raymond; Lehtimaki, Terho; Martin, Nicholas G.; Jarvelin, Marjo- Devereau, Andrew; Patrinos, George P.; Swertz, Morris Riitta; Visscher, Peter M.; Keller, Matthew C.; Zietsch, A.; Taschner, Peter E. M.; Thorisson, Gudmundur A.; Brendan P. In: Evolution, Vol. 66, No. 10, 01.10.2012, p. Vihinen, Mauno; Brookes, Anthony J.; Muilu, Juha. In: 3238-3251. BMC Bioinformatics, Vol. 13, No. Article Number: 254, 03.10.2012. 28. No association between body size at birth and leucocyte telomere length in adult life-evidence 24. A balanced translocation truncates Neurotrimin from three cohort studies. / Kajantie, Eero; Pietilainen, in a family with intracranial and thoracic aortic Kirsi H.; Wehkalampi, Karoliina; Kananen, Laura; aneurysm. / Luukkonen, Tiia M.; Pöyhönen, Minna; Räikkönen, Katri; Rissanen, Aila; Hovi, Petteri; Kaprio, Palotie, Aarno; Ellonen, Pekka; Lagstrom, Sonja; Lee, Jaakko; Andersson, Sture; Eriksson, Johan G.; Hovatta, Joseph H.; Terwilliger, Joseph D.; Salonen, Riitta; Varilo, Iiris. In: International Journal of Epidemiology, Vol. 41, Teppo. In: Journal of Medical Genetics, Vol. 49, No. 10, No. 5, 01.10.2012, p. 1400-1408. 01.10.2012, p. 621-629. 29. Telomere length in blood and skeletal muscle in 25. A meta-analysis of genome-wide association studies relation to measures of glycaemia and insulinaemia. of the electrocardiographic early repolarization / Ahmad, S.; Heraclides, A.; Sun, Q.; Elgzyri, T.; Ronn, T.; pattern. / Sinner, Moritz F.; Porthan, Kimmo; Ling, C.; Isomaa, B.; Eriksson, K-F.; Groop, L.; Franks, P. Noseworthy, Peter A.; Havulinna, Aki S.; Tikkanen, Jani W.; Hansson, O. In: Diabetic Medicine, Vol. 29, No. 10, T.; Mueller-Nurasyid, Martina; Peloso, Gina; Ulivi, Sheila; 01.10.2012, p. e377-e381. Beckmann, Britt Maria; Brockhaus, A. Catharina; Cooper, Rebecca R.; Gasparini, Paolo; Hengstenberg, Christian; 30. Genome-Wide Association Studies of Asthma Hwang, Shih-Jen; Iorio, Annamaria; Junttila, M. Juhani; in Population-Based Cohorts Confirm Known Klopp, Norman; Kahonen, Mika; Laaksonen, Maarit A.; and Suggested Loci and Identify an Additional Lehtimaki, Terho; Lichtner, Peter; Lyytikainen, Leo-Pekka; Association near HLA. / Ramasamy, Adaikalavan; Martens, Eimo; Meisinger, Christa; Meitinger, Thomas; Kuokkanen, Mikko; Vedantam, Sailaja; Gajdos, Zofia Merchant, Faisal M.; Nieminen, Markku S.; Peters, K.; Alves, Alexessander Couto; Lyon, Helen N.; Ferreira, Annette; Pietila, Arto; Perz, Siegfried; Oikarinen, Lasse; Manuel A. R.; Strachan, David P.; Zhao, Jing Hua; Raitakari, Olli; Reinhard, Wibke; Silander, Kaisa; Thorand, Abramson, Michael J.; Brown, Matthew A.; Coin, Lachlan; Barbara; Wichmann, H. -Erich; Sinagra, Gianfranco; Dharmage, Shyamali C.; Duffy, David L.; Haahtela, Viikari, Jorma; O’Donnell, Christopher J.; Ellinor, Patrick Tari; Heath, Andrew C.; Janson, Christer; Kahonen, T.; Huikuri, Heikki V.; Kaeaeb, Stefan; Newton-Cheh, Mika; Khaw, Kay-Tee; Laitinen, Jaana; Le Souef, Peter; Christopher; Salomaa, Veikko. In: Heart rhythm., Vol. 9, Lehtimaki, Terho; Madden, Pamela A. F.; Marks, Guy No. 10, 01.10.2012, p. 1627-1634. B.; Martin, Nicholas G.; Matheson, Melanie C.; Palmer,

70 • FIMM Cameron D.; Palotie, Aarno; Pouta, Anneli; Robertson, M.; Chines, Peter S.; Fischer, Krista; Fontanillas, Pierre; Colin F.; Viikari, Jorma; Widen, Elisabeth; Wjst, Matthias; Holmen, Oddgeir L.; Hunt, Sarah E.; Jackson, Anne U.; Jarvis, Deborah L.; Montgomery, Grant W.; Thompson, Kong, Augustine; Lawrence, Robert; Meyer, Julia; Perry, Philip J.; Wareham, Nick; Eriksson, Johan; Jousilahti, John R. B.; Platou, Carl G. P.; Potter, Simon; Rehnberg, Pekka; Laitinen, Tarja; Pekkanen, Juha; Raitakari, Olli T.; Emil; Robertson, Neil; Sivapalaratnam, Suthesh; O’Connor, George T.; Salomaa, Veikko; Jarvelin, Marjo- Stancakova, Alena; Stirrups, Kathleen; Thorleifsson, Riitta; Hirschhorn, Joel N.; Australian Asthma Genetics. Gudmar; Tikkanen, Emmi; Wood, Andrew R.; Almgren, In: PLoS One, Vol. 7, No. 9, 28.09.2012, p. Article Peter; Atalay, Mustafa; Benediktsson, Rafn; Bonnycastle, Number: e44008. Lori L.; Burtt, Noel; Carey, Jason; Charpentier, Guillaume; Crenshaw, Andrew T.; Doney, Alex S. F.; Dorkhan, 31. The future of technologies for personalised Mozhgan; Edkins, Sarah; Emilsson, Valur; Eury, Elodie; medicine. / Harvey, Alison; Brand, Angela; Holgate, Forsen, Tom; Gertow, Karl; Gigante, Bruna; Grant, George Stephen T.; Kristiansen, Lars V.; Lehrach, Hans; Palotie, B.; Groves, Christopher J.; Guiducci, Candace; Herder, Aarno; Prainsack, Barbara. n: New Biotechnology, Vol. Christian; Hreidarsson, Astradur B.; Hui, Jennie; James, 29, No. 6, 15.09.2012, p. 625-633. Alan; Jonsson, Anna; Rathmann, Wolfgang; Klopp, 32. CIP2A signature reveals the MYC dependency Norman; Kravic, Jasmina; Krjutskov, Kaarel; Langford, of CIP2A-regulated phenotypes and its clinical Cordelia; Leander, Karin; Lindholm, Eero; Lobbens, association with breast cancer subtypes. / Niemela, Stephane; Mannisto, Satu; Mirza, Ghazala; Muehleisen, M.; Kauko, O.; Sihto, H.; Mpindi, J-P; Nicorici, D.; Thomas W.; Musk, Bill; Parkin, Melissa; Rallidis, Pernila, P.; Kallioniemi, O-P; Joensuu, H.; Hautaniemi, Loukianos; Saramies, Jouko; Sennblad, Bengt; Shah, S.; Westermarck, J. In: Oncogene, Vol. 31, No. 39, Sonia; Sigurdsson, Gunnar; Silveira, Angela; Steinbach, 01.09.2012, p. 4266-4278. Gerald; Thorand, Barbara; Trakalo, Joseph; Veglia, Fabrizio; Wennauer, Roman; Winckler, Wendy; Zabaneh, Delilah; 33. High-throughput quantification of circulating Campbell, Harry; van Duijn, Cornelia; Uitterlinden, Andre metabolites improves prediction of subclinical G.; Hofman, Albert; Sijbrands, Eric; Abecasis, Goncalo R.; atherosclerosis. / Wurtz, Peter; Raiko, Juho R.; Owen, Katharine R.; Zeggini, Eleftheria; Trip, Mieke D.; Magnussen, Costan G.; Soininen, Pasi; Kangas, Antti J.; Forouhi, Nita G.; Syvanen, Ann-Christine; Eriksson, Johan Tynkkynen, Tuulia; Thomson, Russell; Laatikainen, Reino; G.; Palotie, Leena; Noethen, Markus M.; Balkau, Beverley; Savolainen, Markku J.; Laurikka, Jari; Kuukasjarvi, Pekka; Palmer, Colin N. A.; Lyssenko, Valeriya; Tuomi, Tiinamaija; Tarkka, Matti; Karhunen, Pekka J.; Jula, Antti; Viikari, Isomaa, Bo; Hunter, David J.; Qi, Lu; Shuldiner, Alan R.; Jorma S.; Kahonen, Mika; Lehtimaki, Terho; Juonala, Roden, Michael; Barroso, Ines; Wilsgaard, Tom; Beilby, Markus; Ala-Korpela, Mika; Raitakari, Olli T. In: European John; Hovingh, Kees; Price, Jackie F.; Wilson, James F.; Heart Journal, Vol. 33, No. 18, 01.09.2012, p. 2307-2316. Rauramaa, Rainer; Lakka, Timo A.; Lind, Lars; Dedoussis, George; Njolstad, Inger; Pedersen, Nancy L.; Khaw, 34. Large-scale association analyses identify new loci Kay-Tee; Wareham, Nicholas J.; Keinanen-Kiukaanniemi, influencing glycemic traits and provide insight Sirkka M.; Saaristo, Timo E.; Korpi-Hyovalti, Eeva; Saltevo, into the underlying biological pathways. / DIAbet Juha; Laakso, Markku; Kuusisto, Johanna; Metspalu, Genetics Replication. In: Nature Genetics, Vol. 44, No. 9, Andres; Collins, Francis S.; Mohlke, Karen L.; Bergman, 01.09.2012, p. 991+. Richard N.; Tuomilehto, Jaakko; Boehm, Bernhard O.; 35. Large-scale association analysis provides insights Gieger, Christian; Hveem, Kristian; Cauchi, Stephane; into the genetic architecture and pathophysiology of Froguel, Philippe; Baldassarre, Damiano; Tremoli, Elena; type 2 diabetes. / Morris, Andrew P.; Voight, Benjamin Humphries, Steve E.; Saleheen, Danish; Danesh, John; F.; Teslovich, Tanya M.; Ferreira, Teresa; Segre, Ayellet V.; Ingelsson, Erik; Ripatti, Samuli; Salomaa, Veikko; Erbel, Steinthorsdottir, Valgerdur; Strawbridge, Rona J.; Khan, Raimund; Joeckel, Karl-Heinz; Moebus, Susanne; Peters, Hassan; Grallert, Harald; Mahajan, Anubha; Prokopenko, Annette; Illig, Thomas; de Faire, Ulf; Hamsten, Anders; Inga; Kang, Hyun Min; Dina, Christian; Esko, Tonu; Fraser, Morris, Andrew D.; Donnelly, Peter J.; Frayling, Timothy M.; Ross M.; Kanoni, Stavroula; Kumar, Ashish; Lagou, Vasiliki; Hattersley, Andrew T.; Boerwinkle, Eric; Melander, Olle; Langenberg, Claudia; Luan, Jian’an; Lindgren, Cecilia M.; Kathiresan, Sekar; Nilsson, Peter M.; Deloukas, Panos; Mueller-Nurasyid, Martina; Pechlivanis, Sonali; Rayner, Thorsteinsdottir, Unnur; Groop, Leif C.; Stefansson, Kari; N. William; Scott, Laura J.; Wiltshire, Steven; Yengo, Loic; Hu, Frank; Pankow, James S.; Dupuis, Josee; Meigs, James Kinnunen, Leena; Rossin, Elizabeth J.; Raychaudhuri, B.; Altshuler, David; Boehnke, Michael; McCarthy, Mark I.; Soumya; Johnson, Andrew D.; Dimas, Antigone S.; Loos, Wellcome Trust Case Control, Meta-Anal Glucose Insulin- Ruth J. F.; Vedantam, Sailaja; Chen, Han; Florez, Jose C.; Related, Genetic Invest ANthropometric, Asian Genetic Fox, Caroline; Liu, Ching-Ti; Rybin, Denis; Couper, David Epidemiology, S Asian Type 2 Diabet SAT2D, DIAbet J.; Kao, Wen Hong L.; Li, Man; Cornelis, Marilyn C.; Kraft, Genetics Replication. In: Nature Genetics, Vol. 44, No. 9, Peter; Sun, Qi; van Dam, Rob M.; Stringham, Heather 01.09.2012, p. 981-990.

FIMM • 71 36. Geenit nivelrikon takana. / Näkki, Annu. In: Niveltieto : Malcolm; Rudan, Igor; Gasparini, Paolo; Pramstaller, Peter Suomen tekonivelyhdistys ry:n jäsenlehti., Vol. 2012, No. P.; Deary, Ian J.; Toniolo, Daniela; Eriksson, Johan G.; Jula, 3, 20.08.2012, p. 5-7. Antti; Raitakari, Olli T.; Metspalu, Andres; Perola, Markus; Jarvelin, Marjo-Riitta; Uitterlinden, Andre; Visscher, 37. Gankyrin promotes breast cancer cell metastasis by Peter M.; Wilson, James F.; ROHgen Consortium. In: regulating Rac1 activity. / Zhen, Chen; Chen, Liang; PLoS Genetics, Vol. 8, No. 7, 07.2012, p. Article Number: Liang, Bing; Gu, Yuexi; Bai, Zhaofang; Wang, Kai; Fang, e1002655. Difeng; Zhou, Tao; Xia, Qing; Gong, Weili; Wang, Na; Li, Huiyan; Jin, Baofeng; Man, Jianghong. In: Oncogene, 42. Comprehensive data-driven analysis of the impact 13.08.2012. of chemoinformatic structure on the genome-wide biological response profiles of cancer cells to 1159 38. Local phase quantization for blur-insensitive image drugs. / Khan, Suleiman A.; Faisal, Ali; Mpindi, John analysis. / Rahtu, Esa; Heikkila, Janne; Ojansivu, Ville; Patrick; Parkkinen, Juuso A.; Kalliokoski, Tuomo; Poso, Ahonen, Timo. In: Image and Vision Computing, Vol. 30, Antti; Kallioniemi, Olli P.; Wennerberg, Krister; Kaski, No. 8, 01.08.2012, p. 501-512. Samuel. In: BMC Bioinformatics, Vol. 13, 30.05.2012, p. Article Number: 112. 39. Novel Loci for Metabolic Networks and Multi-Tissue Expression Studies Reveal Genes for Atherosclerosis. 43. A genome-wide meta-analysis of association studies / Inouye, Michael; Ripatti, Samuli; Kettunen, Johannes; of Cloninger’s Temperament Scales. / Service, S. Lyytikainen, Leo-Pekka; Oksala, Niku; Laurila, Pirkka- K.; Verweij, K. J. H.; Lahti, J.; Congdon, E.; Ekelund, Pekka; Kangas, Antti J.; Soininen, Pasi; Savolainen, J.; Hintsanen, M.; Räikkönen, Katri; Lehtimaki, T.; Markku J.; Viikari, Jorma; Kahonen, Mika; Perola, Kahonen, M.; Widen, E.; Taanila, A.; Veijola, J.; Heath, Markus; Salomaa, Veikko; Raitakari, Olli; Lehtimaki, A. C.; Madden, P. A. F.; Montgomery, G. W.; Sabatti, C.; Terho; Taskinen, Marja-Riitta; Jaervelin, Marjo-Riitta; Jarvelin, M-R; Palotie, A.; Raitakari, O.; Viikari, J.; Martin, Ala-Korpela, Mika; Palotie, Aarno; de Bakker, Paul I. W. N. G.; Eriksson, J. G.; Keltikangas-Järvinen, Liisa; Wray, In: PLoS Genetics, Vol. 8, No. 8, 01.08.2012, p. Article N. R.; Freimer, N. B. In: Translational Psychiatry, Vol. 2, Number: e1002907. 05.2012, p. Article Number: e116.

40. Negative regulators of integrin activity. / Pouwels, 44. Genome-Wide Association for Abdominal Jeroen; Nevo, Jonna; Pellinen, Teijo; Ylanne, Jari; Ivaska, Subcutaneous and Visceral Adipose Reveals a Novel Johanna. In: Journal of Cell Science, Vol. 125, No. 14, Locus for Visceral Fat in Women. / Fox, Caroline S.; Liu, 15.07.2012, p. 3271-3280. Yongmei; White, Charles C.; Feitosa, Mary; Smith, Albert V.; Heard-Costa, Nancy; Lohman, Kurt; Johnson, Andrew 41. Evidence of Inbreeding Depression on Human D.; Foster, Meredith C.; Greenawalt, Danielle M.; Griffin, Height. / McQuillan, Ruth; Eklund, Niina; Pirastu, Nicola; Paula; Ding, Jinghong; Newman, Anne B.; Tylavsky, Fran; Kuningas, Maris; McEvoy, Brian P.; Esko, Tonu; Corre, Miljkovic, Iva; Kritchevsky, Stephen B.; Launer, Lenore; Tanguy; Davies, Gail; Kaakinen, Marika; Lyytikainen, Garcia, Melissa; Eiriksdottir, Gudny; Carr, J. Jeffrey; Leo-Pekka; Kristiansson, Kati; Havulinna, Aki S.; Gogele, Gudnason, Vilmunder; Harris, Tamara B.; Cupples, L. Martin; Vitart, Veronique; Tenesa, Albert; Aulchenko, Yurii; Adrienne; Borecki, Ingrid B.; GIANT Consortium; MAGIC Hayward, Caroline; Johansson, Asa; Boban, Mladen; Ulivi, Consortium; GLGC Consortium ; Ripatti, Samuli Olli; Sheila; Robino, Antonietta; Boraska, Vesna; Igl, Wilmar; Kaprio, Jaakko. In: PLoS Genetics, Vol. 8, No. 5, 05.2012, Wild, Sarah H.; Zgaga, Lina; Amin, Najaf; Theodoratou, p. Article Number: e1002695. Evropi; Polasek, Ozren; Girotto, Giorgia; Lopez, Lorna M.; Sala, Cinzia; Lahti, Jari; Laatikainen, Tiina; Prokopenko, 45. Genome-Wide Screen for Metabolic Syndrome Inga; Kals, Mart; Viikari, Jorma; Yang, Jian; Pouta, Anneli; Susceptibility Loci Reveals Strong Lipid Gene Estrada, Karol; Hofman, Albert; Freimer, Nelson; Martin, Contribution But No Evidence for Common Genetic Nicholas G.; Kahonen, Mika; Milani, Lili; Heliovaara, Basis for Clustering of Metabolic Syndrome Traits. Markku; Vartiainen, Erkki; Räikkönen, Katri; Masciullo, / Kristiansson, Kati; Perola, Markus; Tikkanen, Emmi; Corrado; Starr, John M.; Hicks, Andrew A.; Esposito, Laura; Kettunen, Johannes; Surakka, Ida; Havulinna, Aki S.; Kolcic, Ivana; Farrington, Susan M.; Oostra, Ben; Zemunik, Stancakova, Alena; Barnes, Chris; Widen, Elisabeth; Tatijana; Campbell, Harry; Kirin, Mirna; Pehlic, Marina; Kajantie, Eero; Eriksson, Johan G.; Viikari, Jorma; Faletra, Flavio; Porteous, David; Pistis, Giorgio; Widen, Kahonen, Mika; Lehtimaki, Terho; Raitakari, Olli T.; Elisabeth; Salomaa, Veikko; Koskinen, Seppo; Fischer, Hartikainen, Anna-Liisa; Ruokonen, Aimo; Pouta, Anneli; Krista; Lehtimaki, Terho; Heath, Andrew; McCarthy, Jula, Antti; Kangas, Antti J.; Soininen, Pasi; Ala-Korpela, Mark I.; Rivadeneira, Fernando; Montgomery, Grant W.; Mika; Mannisto, Satu; Jousilahti, Pekka; Bonnycastle, Tiemeier, Henning; Hartikainen, Anna-Liisa; Madden, Lori L.; Jarvelin, Marjo-Riitta; Kuusisto, Johanna; Collins, Pamela A. F.; d’Adamo, Pio; Hastie, Nicholas D.; Gyllensten, Francis S.; Laakso, Markku; Hurles, Matthew E.; Palotie, Ulf; Wright, Alan F.; van Duijn, Cornelia M.; Dunlop, Aarno; Palotie, Leena; Ripatti, Samuli; Salomaa, Veikko.

72 • FIMM In: Circulation, Cardiovascular genetics, Vol. 5, No. 2, Fornage, Myriam; Lagou, Vasiliki; Mangino, Massimo; 04.2012, p. 242-249. Onland-Moret, N. Charlotte; Chen, Brian; Eriksson, Joel; Garcia, Melissa; Mei, Yong; Koster, Annemarie; Lohman, 46. Complement lectin pathway genotypes associated Kurt; Lyytikainen, Leo-Pekka; Petersen, Ann-Kristin; with placental malaria. / Holmberg, Ville; Onkamo, Prescott, Jennifer; Stolk, Lisette; Vandenput, Liesbeth; Paivi; Lahtela, Elisa; Lahermo, Paivi; Mockenhaupt, Frank Wood, Andrew R.; Zhuang, Wei Vivian; Ruokonen, Aimo; P.; Meri, Seppo. In: Cellular & Molecular Immunology, Vol. Hartikainen, Anna-Liisa; Pouta, Anneli; Bandinelli, 2012, No. 11, 02.03.2012, p. 61. Stefania; Biffar, Reiner; Brabant, Georg; Cox, David G.; Chen, Yuhui; Cummings, Steven; Ferrucci, Luigi; 47. A Genome-Wide Association Search for Type 2 Gunter, Marc J.; Hankinson, Susan E.; Martikainen, Diabetes Genes in African Americans. / Palmer, Hannu; Hofman, Albert; Homuth, Georg; Illig, Thomas; Nicholette D.; McDonough, Caitrin W.; Hicks, Pamela Jansson, John-Olov; Johnson, Andrew D.; Karasik, David; J.; Roh, Bong H.; Wing, Maria R.; An, S. Sandy; Hester, Karlsson, Magnus; Kettunen, Johannes; Kiel, Douglas P.; Jessica M.; Cooke, Jessica N.; Bostrom, Meredith A.; Kraft, Peter; Liu, Jingmin; Ljunggren, Osten; Lorentzon, Rudock, Megan E.; Talbert, Matthew E.; Lewis, Joshua Mattias; Maggio, Marcello; Markus, Marcello R. P.; P.; Ferrara, Assiamira; Lu, Lingyi; Ziegler, Julie T.; Sale, Mellstrom, Dan; Miljkovic, Iva; Mirel, Daniel; Nelson, Michele M.; Divers, Jasmin; Shriner, Daniel; Adeyemo, Sarah; Papunen, Laure Morin; Peeters, Petra H. M.; Adebowale; Rotimi, Charles N.; Ng, Maggie C. Y.; Prokopenko, Inga; Raffel, Leslie; Reincke, Martin; Reiner, Langefeld, Carl D.; Freedman, Barry I.; Bowden, Donald Alex P.; Rexrode, Kathryn; Rivadeneira, Fernando; W.; DIAGRAM Consortium; MAGIC Investigators ; Ripatti, Schwartz, Stephen M.; Siscovick, David; Soranzo, Nicole; Samuli Olli; Kaprio, Jaakko. In: PLoS One, Vol. 7, No. 1, Stockl, Doris; Tworoger, Shelley; Uitterlinden, Andre G.; 04.01.2012, p. Article Number:e29202 . van Gils, Carla H.; Vasan, Ramachandran S.; Wichmann, H. -Erich; Zhai, Guangju; Bhasin, Shalender; Bidlingmaier, 48. Genome-wide association study identifies multiple Martin; Chanock, Stephen J.; De Vivo, Immaculata; loci influencing human serum metabolite levels. / Harris, Tamara B.; Hunter, David J.; Kahonen, Mika; Liu, Kettunen, Johannes; Tukiainen, Taru; Sarin, Antti-Pekka; Simin; Ouyang, Pamela; Spector, Tim D.; van der Schouw, Ortega-Alonso, Alfredo; Tikkanen, Emmi; Lyytikäinen, Yvonne T.; Viikari, Jorma; Wallaschofski, Henri; McCarthy, Leo-Pekka; Kangas, Antti J; Soininen, Pasi; Würtz, Mark I.; Frayling, Timothy M.; Murray, Anna; Franks, Peter; Silander, Kaisa; Dick, Danielle M; Rose, Richard Steve; Jarvelin, Marjo-Riitta; de Jong, Frank H.; Raitakari, J; Savolainen, Markku J; Viikari, Jorma; Kähönen, Mika; Olli; Teumer, Alexander; Ohlsson, Claes; Murabito, Lehtimäki, Terho; Pietiläinen, Kirsi H; Inouye, Michael; Joanne M.; Perry, John R. B. In: PLoS Genetics, Vol. 8, No. McCarthy, Mark I; Jula, Antti; Eriksson, Johan; Raitakari, 7, 2012, p. Article Number: e1002805. Olli T; Salomaa, Veikko; Kaprio, Jaakko; Järvelin, Marjo- Riitta; Peltonen, Leena; Perola, Markus; Freimer, Nelson 52. A Genome-Wide Association Study Identifies B; Ala-Korpela, Mika; Palotie, Aarno; Ripatti, Samuli. In: UGT1A1 as a Regulator of Serum Cell-Free DNA in Nature Genetics, 01.01.2012, p. 1-10. Young Adults: The Cardiovascular Risk in Young Finns Study. / Jylhava, Juulia; Lyytikainen, Leo-Pekka; 49. Olemmeko valmiita henkilöityyn lääketieteeseen Kahonen, Mika; Hutri-Kahonen, Nina; Kettunen, ja omiikkatiedon soveltamiseen? / Palotie, Aarno. In: Johannes; Viikari, Jorma; Raitakari, Olli T.; Lehtimaki, Moodi., Vol. 36, No. 1, 01.2012, p. 225-228. Terho; Hurme, Mikko. In: PLoS One, Vol. 7, No. 4, 2012, p. Article Number: e35426. 50. 15-Hydroxyprostaglandin dehydrogenase associates with poor prognosis in breast cancer, induces 53. A common variant near the KCNJ2 gene is epithelial-mesenchymal transition, and promotes associated with T-peak to T-end interval. / Marjamaa, cell migration in cultured breast cancer cells. / Annukka; Oikarinen, Lasse; Porthan, Kimmo; Ripatti, Lehtinen, Laura; Vainio, Paula; Wikman, Harriet; Reemts, Samuli; Peloso, Gina; Noseworthy, Peter A.; Viitasalo, Johannes; Hilvo, Mika; Issa, Rana; Pollari, Sirkku; Brandt, Matti; Nieminen, Markku S.; Kontula, Kimmo; Toivonen, Burkhard; Oresic, Matej; Pantel, Klaus; Kallioniemi, Olli; Lauri; Palotie, Leena; Havulinna, Aki S.; Jula, Antti; Iljin, Kristiina. In: Internet Journal of Pathology, Vol. 226, O’Donnell, Christopher J.; Newton-Cheh, Christopher; No. 4, 2012, p. 674-686. Perola, Markus; Salomaa, Veikko. In: Heart rhythm., Vol. 9, No. 7, 2012, p. 1099-1103. 51. A Genome-Wide Association Meta-Analysis of Circulating Sex Hormone-Binding Globulin Reveals 54. A functional genetic screen reveals new regulators Multiple Loci Implicated in Sex Steroid Hormone of beta 1-integrin activity. / Pellinen, Teijo; Rantala, Regulation. / Coviello, Andrea D.; Haring, Robin; Juha K.; Arjonen, Antti; Mpindi, John Patrick; Kallioniemi, Wellons, Melissa; Vaidya, Dhananjay; Lehtimaki, Terho; Olli; Ivaska, Johanna. In: Journal of Cell Science, Vol. 125, Keildson, Sarah; Lunetta, Kathryn L.; He, Chunyan; No. 3, 2012, p. 649-661.

FIMM • 73 55. A genome-wide approach accounting for body mass Richa; Schwarz, Peter; Seedorf, Udo; Sennblad, Bengt; index identifies genetic variants influencing fasting Serrano-Rios, Manuel; Shuldiner, Alan R.; Sijbrands, Eric glycemic traits and insulin resistance. / Manning, J. G.; Siscovick, David S.; Smit, Johannes H.; Small, Kerrin Alisa K.; Hivert, Marie-France; Scott, Robert A.; Grimsby, S.; Smith, Nicholas L.; Smith, Albert Vernon; Stancakova, Jonna L.; Bouatia-Naji, Nabila; Chen, Han; Rybin, Denis; Alena; Stirrups, Kathleen; Stumvoll, Michael; Sun, Yan Liu, Ching-Ti; Bielak, Lawrence F.; Prokopenko, Inga; V.; Swift, Amy J.; Toenjes, Anke; Tuomilehto, Jaakko; Amin, Najaf; Barnes, Daniel; Cadby, Gemma; Hottenga, Trompet, Stella; Uitterlinden, Andre G.; Uusitupa, Matti; Jouke-Jan; Ingelsson, Erik; Jackson, Anne U.; Johnson, Vikstrom, Max; Vitart, Veronique; Vohl, Marie-Claude; Toby; Kanoni, Stavroula; Ladenvall, Claes; Lagou, Vasiliki; Voight, Benjamin F.; Vollenweider, Peter; Waeber, Lahti, Jari; Lecoeur, Cecile; Liu, Yongmei; Martinez-Larrad, Gerard; Waterworth, Dawn M.; Watkins, Hugh; Wheeler, Maria Teresa; Montasser, May E.; Navarro, Pau; Perry, Eleanor; Widen, Elisabeth; Wild, Sarah H.; Willems, Sara John R. B.; Rasmussen-Torvik, Laura J.; Salo, Perttu; M.; Willemsen, Gonneke; Wilson, James F.; Witteman, Sattar, Naveed; Shungin, Dmitry; Strawbridge, Rona J.; Jacqueline C. M.; Wright, Alan F.; Yaghootkar, Hanieh; Tanaka, Toshiko; van Duijn, Cornelia M.; An, Ping; de Zelenika, Diana; Zemunik, Tatijana; Zgaga, Lina; Andrade, Mariza; Andrews, Jeanette S.; Aspelund, Thor; Wareham, Nicholas J.; McCarthy, Mark I.; Barroso, Atalay, Mustafa; Aulchenko, Yurii; Balkau, Beverley; Ines; Watanabe, Richard M.; Florez, Jose C.; Dupuis, Bandinelli, Stefania; Beckmann, Jacques S.; Beilby, Josee; Meigs, James B.; Langenberg, Claudia; MUTHER John P.; Bellis, Claire; Bergman, Richard N.; Blangero, Consortium, DIAGRAM Consortium. In: Nature Genetics, John; Boban, Mladen; Boehnke, Michael; Boerwinkle, Vol. 44, No. 6, 2012, p. 659-U81. Eric; Bonnycastle, Lori L.; Boomsma, Dorret I.; Borecki, 56. A genome-wide association meta-analysis identifies Ingrid B.; Boettcher, Yvonne; Bouchard, Claude; Brunner, new childhood obesity loci. / Bradfield, Jonathan Eric; Budimir, Danijela; Campbell, Harry; Carlson, Olga; P.; Taal, H. Rob; Timpson, Nicholas J.; Scherag, Andre; Chines, Peter S.; Clarke, Robert; Collins, Francis S.; Lecoeur, Cecile; Warrington, Nicole M.; Hypponen, Elina; Corbaton-Anchuelo, Arturo; Couper, David; de Faire, Ulf; Holst, Claus; Valcarcel, Beatriz; Thiering, Elisabeth; Dedoussis, George V.; Deloukas, Panos; Dimitriou, Maria; Salem, Rany M.; Schumacher, Fredrick R.; Cousminer, Egan, Josephine M.; Eiriksdottir, Gudny; Erdos, Michael Diana L.; Sleiman, Patrick M. A.; Zhao, Jianhua; R.; Eriksson, Johan G.; Eury, Elodie; Ferrucci, Luigi; Ford, Berkowitz, Robert I.; Vimaleswaran, Karani S.; Jarick, Ian; Forouhi, Nita G.; Fox, Caroline S.; Franzosi, Maria Ivonne; Pennell, Craig E.; Evans, David M.; St Pourcain, Grazia; Franks, Paul W.; Frayling, Timothy M.; Froguel, Beate; Berry, Diane J.; Mook-Kanamori, Dennis O.; Philippe; Galan, Pilar; de Geus, Eco; Gigante, Bruna; Hofman, Albert; Rivadeneira, Fernando; Uitterlinden, Glazer, Nicole L.; Goel, Anuj; Groop, Leif; Gudnason, Andre G.; van Duijn, Cornelia M.; van der Valk, Ralf J. Vilmundur; Hallmans, Goeran; Hamsten, Anders; P.; de Jongste, Johan C.; Postma, Dirkje S.; Boomsma, Hansson, Ola; Harris, Tamara B.; Hayward, Caroline; Dorret I.; Gauderman, W. James; Hassanein, Mohamed Heath, Simon; Hercberg, Serge; Hicks, Andrew A.; T.; Lindgren, Cecilia M.; Magi, Reedik; Boreham, Colin Hingorani, Aroon; Hofman, Albert; Hui, Jennie; Hung, A. G.; Neville, Charlotte E.; Moreno, Luis A.; Elliott, Paul; Joseph; Jarvelin, Marjo-Riitta; Jhun, Min A.; Johnson, Paul Pouta, Anneli; Hartikainen, Anna-Liisa; Li, Mingyao; C. D.; Jukema, J. Wouter; Jula, Antti; Kao, W. H.; Kaprio, Raitakari, Olli; Lehtimaki, Terho; Eriksson, Johan G.; Jaakko; Kardia, Sharon L. R.; Keinanen-Kiukaanniemi, Palotie, Aarno; Dallongeville, Jean; Das, Shikta; Deloukas, Sirkka; Kivimaki, Mika; Kolcic, Ivana; Kovacs, Peter; Panos; McMahon, George; Ring, Susan M.; Kemp, Kumari, Meena; Kuusisto, Johanna; Kyvik, Kirsten Ohm; John P.; Buxton, Jessica L.; Blakemore, Alexandra I. F.; Laakso, Markku; Lakka, Timo; Lannfelt, Lars; Lathrop, Bustamante, Mariona; Guxens, Monica; Hirschhorn, Joel G. Mark; Launer, Lenore J.; Leander, Karin; Li, Guo; Lind, N.; Gillman, Matthew W.; Kreiner-Moller, Eskil; Bisgaard, Lars; Lindstrom, Jaana; Lobbens, Stephane; Loos, Ruth Hans; Gilliland, Frank D.; Heinrich, Joachim; Wheeler, J. F.; Luan, Jian’an; Lyssenko, Valeriya; Magi, Reedik; Eleanor; Barroso, Ines; O’Rahilly, Stephen; Meirhaeghe, Magnusson, Patrik K. E.; Marmot, Michael; Meneton, Aline; Sorensen, Thorkild I. A.; Power, Chris; Palmer, Lyle Pierre; Mohlke, Karen L.; Mooser, Vincent; Morken, J.; Hinney, Anke; Widen, Elisabeth; Farooqi, I. Sadaf; Mario A.; Miljkovic, Iva; Narisu, Narisu; O’Connell, Jeff; McCarthy, Mark I.; Froguel, Philippe; Meyre, David; Ong, Ken K.; Oostra, Ben A.; Palmer, Lyle J.; Palotie, Hebebrand, Johannes; Jarvelin, Marjo-Riitta; Jaddoe, Aarno; Pankow, James S.; Peden, John F.; Pedersen, Vincent W. V.; Smith, George Davey; Hakonarson, Hakon; Nancy L.; Pehlic, Marina; Peltonen, Leena; Penninx, Grant, Struan F. A.; Early Growth Genetics EGG Consorti. Brenda; Pericic, Marijana; Perola, Markus; Perusse, Louis; In: Nature Genetics, Vol. 44, No. 5, 2012, p. 526-+. Peyser, Patricia A.; Polasek, Ozren; Pramstaller, Peter P.; Province, Michael A.; Räikkönen, Katri; Rauramaa, 57. A web-based prognostic tool for extremity and trunk Rainer; Rehnberg, Emil; Rice, Ken; Rotter, Jerome I.; wall soft tissue sarcomas and its external validation. Rudan, Igor; Ruokonen, Aimo; Saaristo, Timo; Sabater- / Sampo, Mika Matias; Tarkkanen, Maija; Tukiainen, Lleal, Maria; Salomaa, Veikko; Savage, David B.; Saxena, E.; Popov, P.; Gustafson, P.; Lundin, M.; Böhling, Tom;

74 • FIMM Blomqvist, C.; Lundin, Johan Edvard. In: British Journal of 65. CIP2A overexpression is associated with c-Myc Cancer, Vol. 106, No. 6, 2012, p. 1076-1082. expression in colorectal cancer. / Böckelman, Camilla; Koskensalo, Selja; Hagström, Jaana; Lundin, Mikael 58. Adipose tissue gene expression analysis reveals Edvard; Ristimäki, Ari; Haglund, Caj. In: Cancer Biology & changes in inflammatory, mitochondrial respiratory Therapy, Vol. 13, No. 5, 2012, p. 289 - 295. and lipid metabolic pathways in obese insulin- resistant subjects. / Soronen, Jarkko; Laurila, Pirkka- 66. Causes and consequences of obesity: the Pekka; Naukkarinen, Jussi; Surakka, Ida; Ripatti, Samuli; contribution of recent twin studies. / Naukkarinen, Jauhiainen, Matti; Olkkonen, Vesa M.; Yki-Järvinen, Jussi; Rissanen, Aila; Kaprio, Jaakko; Pietiläinen, Kirsi Hannele. In: BMC medical genomics, Vol. 5, No. 9, 2012, Hannele. In: International Journal of Obesity, Vol. 36, No. p. Article Number: 9. 8, 2012, p. 1017-1024.

59. An integrated genomic approach identifies ARID1A 67. Childhood Physical, Environmental, and Genetic as a candidate tumor-suppressor gene in breast Predictors of Adult Hypertension The Cardiovascular cancer. / Mamo, A.; Cavallone, L.; Tuzmen, S.; Chabot, Risk in Young Finns Study. / Juhola, Jonna; Oikonen, C.; Ferrario, C.; Hassan, S.; Edgren, H.; Kallioniemi, O.; Mervi; Magnussen, Costan G.; Mikkilä, Vera; Siitonen, Aleynikova, O.; Przybytkowski, E.; Malcolm, K.; Mousses, Niina; Jokinen, Eero; Laitinen, Tomi; Wurtz, Peter; S.; Tonin, P. N.; Basik, M. In: Oncogene, Vol. 31, No. 16, Gidding, Samuel S.; Taittonen, Leena; Seppala, Ilkka; Jula, 2012, p. 2090-2100. Antti; Kahonen, Mika; Hutri-Kahonen, Nina; Lehtimaki, Terho; Viikari, Jorma S. A.; Juonala, Markus; Raitakari, 60. Association Study of Nonsynonymous Single Olli T. In: Circulation (Baltimore), Vol. 126, No. 4, 2012, p. Nucleotide Polymorphisms in Schizophrenia. / 402-409. Carrera, Noa; Arrojo, Manuel; Sanjuan, Julio; Ramos-Rios, Ramon; Paz, Eduardo; Suarez-Rama, Jose J.; Paramo, 68. Circulating Anti-Mullerian Hormone Levels in Mario; Agra, Santiago; Brenlla, Julio; Martinez, Silvia; Adult Men Are under a Strong Genetic Influence. Rivero, Olga; Collier, David A.; Palotie, Aarno; Cichon, / Pietiläinen, Kirsi Hannele; Kaprio, Jaakko; Vaaralahti, Sven; Noethen, Markus M.; Rietschel, Marcella; Rujescu, Kirsi; Rissanen, Aila; Raivio, Taneli. In: Journal of Clinical Dan; Stefansson, Hreinn; Steinberg, Stacy; Sigurdsson, Endocrinology and Metabolism, Vol. 97, No. 1, 2012, p. Engilbert; St Clair, David; Tosato, Sarah; Werge, Thomas; E161-E164. Stefansson, Kari; Carlos Gonzalez, Jose; Valero, Joaquin; Gutierez-Zotes, Alfonso; Labad, Antonio; Martorell, 69. Circulating Meitabolite Predictors of Glycemia in Lourdes; Vilella, Elisabet; Carracedo, Angel; Costas, Javier. Middle-Aged Men and Women. / Wurtz, Peter; Tiainen, In: Biological Psychiatry, Vol. 71, No. 2, 2012, p. 169-177. Mika; Mäkinen, Ville-Petteri; Kangas, Antti J.; Soininen, Pasi; Saltevo, Juha; Keinanen-Kiukaanniemi, Sirkka; 61. Association between depressive symptoms Mantyselka, Pekka; Lehtimaki, Terho; Laakso, Markku; Jula, and metabolic syndrome is not explained by Antti; Kahonen, Mika; Vanhala, Mauno; Ala-Korpela, Mika. antidepressant medication: Results from the PPP- In: Diabetes Care, Vol. 35, No. 8, 2012, p. 1749-1756. Botnia Study. / Pyykkönen, Antti-Jussi; Räikkönen, Katri; Tuomi, Tiinamaija; Eriksson, Johan G.; Groop, Leif; Isomaa, 70. Cln5-deficiency in mice leads to microglial activation, Bo. In: Annals of Medicine, Vol. 44, No. 3, 2012, p. 279-288. defective myelination and changes in lipid metabolism. / Schmiedt, Mia-Lisa; Blom, Tea Susanna; 62. Association of celiac disease genes with Blom, Jan Tomas; Kopra, Outi; Andrew, Wong; von inflammatory bowel disease in Finnish and Swedish Schantz-Fant, Carina; Ikonen, Elina Maria; Kuronen, Mervi; patients. / Parmar, Amarjit; Lappalainen, Anne Maarit; Jauhiainen, Matti; Cooper, Jonathan D.; Jalanko, Anu. In: Paavola-Sakki, Anu Liisa Paulina; Halme, Leena; Färkkilä, Neurobiology of Disease, Vol. 46, No. 1, 2012, p. 19-29. Martti Antero; Turunen, Ulla; Kontula, Kimmo; Aromaa, A; Salomaa, V; Palotie, Leena; Halfvarson, J; Törkvist, 71. Common variants at 12q15 and 12q24 are L; D´Amato, Mauro; Saavalainen, Päivi Marjaana; associated with infant head circumference. / Taal, Einarsdottir, Elisabet. In: Genes and Immunity, Vol. 13, H. Rob; St Pourcain, Beate; Thiering, Elisabeth; Das, No. 6, 2012, p. 474-480. Shikta; Mook-Kanamori, Dennis O.; Warrington, Nicole 63. Automated image analysis of cancer tissue adapted M.; Kaakinen, Marika; Kreiner-Moller, Eskil; Bradfield, for virtual microscopy. / Konsti, Juho. Helsinki : Jonathan P.; Freathy, Rachel M.; Geller, Frank; Guxens, Helsingin Yliopisto, 2012. 69 p. (Helsinki University Monica; Kerkhof, Marjan; Timpson, Nicholas J.; Ikram, Biomedical Dissertations; 174). M. Arfan; Beilin, Lawrence J.; Bonnelykke, Klaus; Buxton, Jessica L.; Charoen, Pimphen; Chawes, Bo Lund 64. Biopankki - osa potilaiden hyvää hoitoa 2012. / Krogsgaard; Eriksson, Johan; Evans, David M.; Hofman, Pitkänen, Kimmo Petri Juhani; Porkka, Kimmo. In: Albert; Kemp, John P.; Kim, Cecilia E.; Klopp, Norman; Duodecim, Vol. 128, No. 16, 2012, p. 1628-1629. Lahti, Jari; Lye, Stephen J.; McMahon, George; Mentch,

FIMM • 75 Frank D.; Mueller-Nurasyid, Martina; O’Reilly, Paul F.; Berry, Diane; Bradfield, Jonathan P.; Charoen, Pimphen; Prokopenko, Inga; Rivadeneira, Fernando; Steegers, Eric Coin, Lachlan; Cousminer, Diana L.; Das, Shikta; Elliott, A. P.; Sunyer, Jordi; Tiesler, Carla; Yaghootkar, Hanieh; Paul; Evans, David M.; Frayling, Tim; Freathy, Rachel M.; Breteler, Monique M. B.; Debette, Stephanie; Fornage, Gaillard, Romy; Groen-Blokhuis, Maria; Guxens, Monica; Myriam; Gudnason, Vilmundur; Launer, Lenore J.; van der Hadley, Dexter; Hottenga, Jouke Jan; Huikari, Ville; Lugt, Aad; Mosley, Thomas H.; Seshadri, Sudha; Smith, Hypponen, Elina; Kaakinen, Marika; Kowgier, Matthew; Albert V.; Vernooij, Meike W.; Blakemore, Alexandra I. Lawlor, Debbie A.; Lewin, Alex; Lindgren, Cecilia; Marsh, F.; Chiavacci, Rosetta M.; Feenstra, Bjarke; Fernandez- Julie; Middeldorp, Christel; Millwood, Iona; Mook- Banet, Julio; Grant, Struan F. A.; Hartikainen, Anna-Liisa; Kanamori, Dennis O.; Nivard, Michel; O’Reilly, Paul F.; van der Heijden, Albert J.; Iniguez, Carmen; Lathrop, Palmer, Lyle J.; Prokopenko, Inga; Rodriguez, Alina; Mark; McArdle, Wendy L.; Molgaard, Anne; Newnham, Sebert, Sylvain; Sovio, Ulla; St Pourcain, Beate; Standl, John P.; Palmer, Lyle J.; Palotie, Aarno; Pouta, Annneli; Marie; Strachan, David P.; Sunyer, Jordi; Taal, H. Rob; Ring, Susan M.; Sovio, Ulla; Standl, Marie; Uitterlinden, Thiering, Elisabeth; Tiesler, Carla; Uitterlinden, Andre G.; Andre G.; Wichmann, H-Erich; Vissing, Nadja Hawwa; Valcarcel, Beatriz; Warrington, Nicole M.; White, Scott; DeCarli, Charles; van Duijn, Cornelia M.; McCarthy, Mark Willemsen, Gonneke; Yaghootkar, Hanieh; Boomsma, I.; Koppelman, Gerard H.; Estivill, Xavier; Hattersley, Dorret I.; Estivill, Xavier; Grant, Struan F. A.; Hakonarson, Andrew T.; Melbye, Mads; Bisgaard, Hans; Pennell, Hakon; Hattersley, Andrew T.; Heinrich, Joachim; Jaddoe, Craig E.; Hakonarson, Hakon; Smith, George Davey; Vincent W. V.; Jarvelin, Marjo-Riitta; McCarthy, Mark Heinrich, Joachim; Jarvelin, Marjo-Riitta; Jaddoe, Vincent I.; Pennell, Craig E.; Power, Chris; Timpson, Nicholas J.; W. V.; Adair, Linda S.; Ang, Wei; Atalay, Mustafa; van Widen, Elisabeth; Ikram, M. Arfan; Fornage, Myriam; Beijsterveldt, Toos; Bergen, Nienke; Benke, Kelly; Berry, Smith, Albert V.; Seshadri, Sudha; Schmidt, Reinhold; Diane; Bradfield, Jonathan P.; Charoen, Pimphen; Coin, Debette, Stephanie; Vrooman, Henri A.; Sigurdsson, Lachlan; Das, Shikta; Davis, Oliver S. P.; Elliott, Paul; Sigurdur; Ropele, Stefan; Coker, Laura H.; Longstreth, Evans, David M.; Feenstra, Bjarke; Flexeder, Claudia; W. T.; Niessen, Wiro J.; DeStefano, Anita L.; Beiser, Alexa; Frayling, Tim; Freathy, Rachel M.; Gaillard, Romy; Zijdenbos, Alex P.; Struchalin, Maksim; Jack, Clifford R.; Geller, Frank; Groen-Blokhuis, Maria; Goh, Liang-Kee; Nalls, Mike A.; Au, Rhoda; Hofman, Albert; Gudnason, Guxens, Monica; Haworth, Claire M. A.; Hadley, Dexter; Haukur; van der Lugt, Aad; Harris, Tamara B.; Meeks, Hedebrand, Johannes; Hinney, Anke; Hirschhorn, Joel William M.; Vernooij, Meike W.; van Buchem, Mark A.; N.; Holloway, John W.; Holst, Claus; Hottenga, Jouke Catellier, Diane; Gudnason, Vilmundur; Windham, B. Jan; Horikoshi, Momoko; Huikari, Ville; Hypponen, Gwen; Wolf, Philip A.; van Duijn, Cornelia M.; Mosley, Elina; Iniguez, Carmen; Kaakinen, Marika; Kilpelainen, Thomas H.; Schmidt, Helena; Launer, Lenore J.; Breteler, Tuomas O.; Kirin, Mirna; Kowgier, Matthew; Lakka, Monique M. B.; DeCarli, Charles; Early Genetics Hanna-Maaria; Lange, Leslie A.; Lawlor, Debbie A.; Lifecourse Epidemio, Early Growth Genetics EGG Lehtimaki, Terho; Lewin, Alex; Lindgren, Cecilia; Lindi, Consorti, Cohorts Heart Aging Res Genetic Ep. In: Nature Virpi; Maggi, Reedik; Marsh, Julie; Middeldorp, Christel; Genetics, Vol. 44, 2012, p. 532-+. Millwood, Iona; Mook-Kanamori, Dennis O.; Murray, 72. Cytokinesis failure due to derailed integrin traffic Jeffrey C.; Nivard, Michel; Nohr, Ellen Aagaard; Ntalla, induces aneuploidy and oncogenic transformation Ioanna; Oken, Emily; O’Reilly, Paul F.; Palmer, Lyle J.; in vitro and in vivo. / Hognas, G.; Tuomi, S.; Veltel, S.; Panoutsopoulou, Kalliope; Pararajasingham, Jennifer; Mattila, E.; Murumägi, Astrid; Edgren, H.; Kallioniemi, O.; Prokopenko, Inga; Rodriguez, Alina; Salem, Rany M.; Ivaska, J. In: Oncogene, Vol. 31, No. 31, 2012, p. 3597- Sebert, Sylvain; Siitonen, Niina; Sovio, Ulla; St Pourcain, 3606. Beate; Strachan, David P.; Sunyer, Jordi; Taal, H. Rob; Teo, Yik-Ying; Thiering, Elisabeth; Tiesler, Carla; Uitterlinden, 73. DISC1 Conditioned GWAS for Psychosis Proneness in Andre G.; Valcarcel, Beatriz; Warrington, Nicole M.; a Large Finnish Birth Cohort. / Tomppo, Liisa; Ekelund, White, Scott; Willemsen, Gonneke; Yaghootkar, Hanieh; Jesper; Lichtermann, Dirk; Veijola, Juha; Jaervelin, Marjo- Zeggini, Eleftheria; Boomsma, Dorret I.; Cooper, Cyrus; Riitta; Hennah, William. In: PLoS One, Vol. 7, No. 2, Estivill, Xavier; Gillman, Matthew; Grant, Struan F. A.; 2012, p. e30643. Hakonarson, Hakon; Hattersley, Andrew T.; Heinrich, 74. Decreased xanthine oxidoreductase (XOR) is Joachim; Hocher, Berthold; Jaddoe, Vincent W. V.; associated with a worse prognosis in patients with Jarvelin, Marjo-Riitta; Lakka, Timo A.; McCarthy, Mark I.; serous ovarian carcinoma. / Linder, Nina; Butzow, Melbye, Mads; Mohlke, Karen L.; Dedoussis, George V.; Ralf; Lassus, Heini; Lundin, Mikael; Lundin, Johan. In: Ong, Ken K.; Pearson, Ewan R.; Pennell, Craig E.; Price, Gynecologic Oncology, Vol. 124, No. 2, 2012, p. 311-318. Thomas S.; Power, Chris; Raitakari, Olli T.; Saw, Seang- Mei; Scherag, Andre; Simell, Olli; Sorensen, Thorkild I. 75. Detailed metabolic and genetic characterization A.; Timpson, Nicholas J.; Wilson, James F.; Ang, Wei; reveals new associations for 30 known lipid loci. van Beijsterveldt, Toos; Bergen, Nienke; Benke, Kelly; / Tukiainen, Taru; Kettunen, Johannes; Kangas, Antti

76 • FIMM J.; Lyytikainen, Leo-Pekka; Soininen, Pasi; Sarin, Antti- 83. Fast and Parallelized Greedy Forward Selection Pekka; Tikkanen, Emmi; O’Reilly, Paul F.; Savolainen, of Genetic Variants in Genome-Wide Association Markku J.; Kaski, Kimmo; Pouta, Anneli; Jula, Antti; Studies. / Okser, Sebastian; Pahikkala, Tapio; Airola, Antti; Lehtimaki, Terho; Kahonen, Mika; Viikari, Jorma; Aittokallio, Tero; Salakoski, Tapio. 2012, p. 214-217. Taskinen, Marja-Riitta; Jauhiainen, Matti; Eriksson, Johan G.; Raitakari, Olli; Salomaa, Veikko; Jarvelin, Marjo- 84. Fetal growth, omega-3 (n−3) fatty acids, and Riitta; Perola, Markus; Palotie, Aarno; Ala-Korpela, Mika; progression of subclinical atherosclerosis: Ripatti, Samuli. In: Human Molecular Genetics, Vol. 21, preventing fetal origins of disease? The No. 6, 2012, p. 1444-1455. Cardiovascular Risk in Young Finns Study. / Skilton, Michael R; Mikkilä, Vera; Würtz, Peter; Ala-Korpela, 76. Discovery of new treatments in the context of Mika; Sim, Kyra A; Soininen, Pasi; Kangas, Antti J; Viikari, delivering personalized medicine. / Holgate, Stephen; Jorma Sa; Juonala, Markus; Laitinen, Tomi; Lehtimäki, Palotie, Aarno. In: Personalized Medicine, Vol. 9, No. 2, Terho; Taittonen, Leena; Kähönen, Mika; Celermajer, 2012, p. 101-104. David S; Raitakari, Olli T. In: American Journal of Clinical Nutrition, 2012. 77. Does dieting make you fat? : A twin study. / Pietilainen, K. H.; Saarni, S. E.; Kaprio, J.; Rissanen, A. In: 85. Genetic Profiling Using Genome-Wide Significant International Journal of Obesity, Vol. 36, No. 3, 2012, p. Coronary Artery Disease Risk Variants Does Not 456-464. Improve the Prediction of Subclinical Atherosclerosis: The Cardiovascular Risk in Young Finns Study, the 78. Early Environment and Neurobehavioral Bogalusa Heart Study and the Health 2000 Survey Development Predict Adult Temperament Clusters. - A Meta-Analysis of Three Independent Studies. / / Congdon, Eliza; Service, Susan; Wessman, Jaana; Hernesniemi, Jussi A.; Seppala, Ilkka; Lyytikainen, Leo- Seppanen, Jouni K.; Schönauer, Stefan; Miettunen, Pekka; Mononen, Nina; Oksala, Niku; Hutri-Kahonen, Jouko; Turunen, Hannu; Koiranen, Markku; Joukamaa, Nina; Juonala, Markus; Taittonen, Leena; Smith, Erin N.; Matti; Jarvelin, Marjo-Riitta; Palotie, Leena; Veijola, Juha; Schork, Nicholas J.; Chen, Wei; Srinivasan, Sathanur R.; Mannila, Heikki; Paunio, Tiina; Freimer, Nelson B. In: PLoS Berenson, Gerald S.; Murray, Sarah S.; Laitinen, Tomi; Jula, One, Vol. 7, No. 7 , 2012, p. Article Number: e38065. Antti; Kettunen, Johannes; Ripatti, Samuli; Laaksonen, Reijo; Viikari, Jorma; Kahonen, Mika; Raitakari, Olli T.; 79. Effect of image compression and scaling on Lehtimaki, Terho. In: PLoS One, Vol. 7, No. 1, 2012, p. automated scoring of immunohistochemical e28931. stainings and segmentation of tumor epithelium. / Konsti, Juho; Lundin, Mikael; Linder, Nina; Haglund, Caj; 86. Genetic Regulation of Pubertal Timing: Implications Blomqvist, Carl; Nevanlinna, Heli; Aaltonen, Kirsimari; for Growth. / Widen, Elisabeth Ingrid Maria. In: In: Nordling, Stig; Lundin, Johan. In: Diagnostic Pathology, Handbook of Growth and Growth Monitoring in Vol. 7, No. Article Number: 29, 2012. Health and Disease.. ed. / Victor R. Preedy. Springer Science+Business Media, 2012. p. 1057-1073. 80. Emerging cellular targets for potential influenza antivirals. / Mueller, Konstantin; Kakkola, Laura; 87. Genetic and Environmental Factors Influencing Nagaraj, Ashwini Sakrepatna; Cheltsov, Anton; BMI Development from Adolescence to Young Anastasina, Maria; Kainov, Denis. In: Trends in Adulthood. / Ortega-Alonso, Alfredo; Pietiläinen, Kirsi H; Pharmacological Sciences, Vol. 33, No. 2, 2012, p. 89-99. Silventoinen, Karri; Saarni, Suoma E; Kaprio, Jaakko. In: Behavior Genetics, Vol. 42, No. 1, 2012, p. 73-85. 81. Enhanced serine production by bone metastatic breast cancer cells stimulates osteoclastogenesis 88. Genetic association and linkage studies in (vol 125, pg 421, 2011). / Pollari, Sirkku; Kakonen, osteoarthritis. / Näkki, Annu Elina; Männikkö, Minna; Sanna-Maria; Edgren, Henrik; Wolf, Maija; Kohonen, Saarela, Janna. In: In: Principles of Osteoarthritis- Its Pekka; Sara, Henri; Guise, Theresa; Nees, Matthias; Definition, Character, Derivation and Modality-Related Kallioniemi, Olli. In: Breast Cancer Research and Recognition. InTech, 2012. Treatment, Vol. 131, No. 3, 2012, p. 1085-1086. 89. Genetic contribution to sour taste preference. / 82. Epicardial Fat, Cardiac Dimensions, and Low-Grade Tornwall, Outi; Silventoinen, Karri; Keskitalo-Vuokko, Inflammation in Young Adult Monozygotic Twins Kaisu; Perola, Markus; Kaprio, Jaakko; Tuorila, Hely. In: Discordant for Obesity. / Graner, Marit Anneli; Seppälä- Appetite, Vol. 58, No. 2, 2012, p. 687-694. Lindroos, Anneli; Rissanen, Aila; Hakkarainen, Antti; Lundbom, Nina; Kaprio, Jaakko; Nieminen, Markku 90. Genetic structure in Finland and Sweden: aspects S.; Pietiläinen, Kirsi Hannele. In: American Journal of of population history and gene mapping. / Salmela, Cardiology, Vol. 109, No. 9, 2012, p. 1295-1302. Elina. Helsinki : [E. Salmela], 2012. 136 p.

FIMM • 77 91. Genome-Wide Association Study to Identify Kettunen, Johannes; Tukiainen, Taru; Sarin, Antti-Pekka; Common Variants Associated with Brachial Ortega-Alonso, Alfredo; Tikkanen, Emmi; Lyytikainen, Circumference: A Meta-Analysis of 14 Cohorts. Leo-Pekka; Kangas, Antti J.; Soininen, Pasi; Wuertz, / Boraska, Vesna; Day-Williams, Aaron; Franklin, Peter; Silander, Kaisa; Dick, Danielle M.; Rose, Richard Christopher S.; Elliott, Katherine S.; Panoutsopoulou, J.; Savolainen, Markku J.; Viikari, Jorma; Kahonen, Mika; Kalliope; Tachmazidou, Ioanna; Albrecht, Eva; Bandinelli, Lehtimaki, Terho; Pietilainen, Kirsi H.; Inouye, Michael; Stefania; Beilin, Lawrence J.; Bochud, Murielle; Cadby, McCarthy, Mark I.; Jula, Antti; Eriksson, Johan; Raitakari, Gemma; Ernst, Florian; Evans, David M.; Hayward, Olli T.; Salomaa, Veikko; Kaprio, Jaakko; Jarvelin, Marjo- Caroline; Hicks, Andrew A.; Huffman, Jennifer; Huth, Riitta; Peltonen, Leena; Perola, Markus; Freimer, Nelson Cornelia; James, Alan L.; Klopp, Norman; Kolcic, Ivana; B.; Ala-Korpela, Mika; Palotie, Aarno; Ripatti, Samuli. In: Kutalik, Zoltan; Lawlor, Debbie A.; Musk, Arthur W.; Nature Genetics, Vol. 44, No. 3, 2012, p. 269-276. Pehlic, Marina; Pennell, Craig E.; Perry, John R. B.; Peters, Annette; Polasek, Ozren; St Pourcain, Beate; Ring, 95. HES6 gene is selectively overexpressed in glioma Susan M.; Salvi, Erika; Schipf, Sabine; Staessen, Jan A.; and represents an important transcriptional Teumer, Alexander; Timpson, Nicholas; Vitart, Veronique; regulator of glioma proliferation. / Haapa-Paananen, Warrington, Nicole M.; Yaghootkar, Hanieh; Zemunik, S.; Kiviluoto, S.; Waltari, Marika Johanna; Puputti, Tatijana; Zgaga, Lina; An, Ping; Anttila, Verneri; Borecki, Marjut; Mpindi, John Patrick; Kohonen, P.; Tynninen, Olli; Ingrid B.; Holmen, Jostein; Ntalla, Ioanna; Palotie, Aarno; Haapasalo, H.; Joensuu, Heikki; Perälä, M.; Kallioniemi, Pietiläinen, Kirsi Hannele; Wedenoja, Juho; Winsvold, Olli-Pekka. In: Oncogene, Vol. 31, No. 10, 2012, p. 1299- Bendik S.; Dedoussis, George V.; Kaprio, Jaakko; Province, 1310. Michael A.; Zwart, John-Anker; Burnier, Michel; Campbell, 96. Heparin-like Polysaccharides Reduce Osteolytic Harry; Cusi, Daniele; Smith, George Davey; Frayling, Bone Destruction and Tumor Growth in a Mouse Timothy M.; Gieger, Christian; Palmer, Lyle J.; Pramstaller, Model of Breast Cancer Bone Metastasis. / Pollari, Peter P.; Rudan, Igor; Voelzke, Henry; Wichmann, H. Sirkku; Kakonen, Rami S.; Mohammad, Khalid S.; Erich; Wright, Alan F.; Zeggini, Eleftheria. In: PLoS One, Rissanen, Jukka P.; Halleen, Jussi M.; Warri, Anni; Vol. 7, No. 3, 2012, p. Article Number: e31369. Nissinen, Liisa; Pihlavisto, Marjo; Marjamaki, Anne; 92. Genome-wide association analysis identifies Perala, Merja; Guise, Theresa A.; Kallioniemi, Olli; susceptibility loci for migraine without aura. / Kakonen, Sanna-Maria. In: Molecular Cancer Research, Freilinger, Tobias; Anttila, Verneri; de Vries, Boukje; Malik, Vol. 10, No. 5, 2012, p. 597-604. Rainer; Kallela, Kaarlo Mikko Juhani; Terwindt, Gisela 97. High prevalence and breast cancer predisposing M.; Pozo-Rosich, Patricia; Winsvold, Bendik; Nyholt, role of the BLM c.1642 C > T (Q548X) mutation Dale R.; van Oosterhout, Willebrordus P. J.; Artto, Ville; in Russia. / Sokolenko, Anna P.; Iyevleva, Aglaya G.; Todt, Unda; Hamalainen, Eija; Fernandez-Morales, Preobrazhenskaya, Elena V.; Mitiushkina, Nathalia V.; Jessica; Louter, Mark A.; Kaunisto, Mari A.; Schoenen, Abysheva, Svetlana N.; Suspitsin, Evgeny N.; Kuligina, Jean; Raitakari, Olli; Lehtimaki, Terho; Vila-Pueyo, Ekatherina Sh.; Gorodnova, Tatiana V.; Pfeifer, Werner; Marta; Goebel, Hartmut; Wichmann, Erich; Sintas, Celia; Togo, Alexandr V.; Turkevich, Elena A.; Ivantsov, Alexandr Uitterlinden, Andre G.; Hofman, Albert; Rivadeneira, O.; Voskresenskiy, Dmitry V.; Dolmatov, Georgy D.; Bit- Fernando; Heinze, Axel; Tronvik, Erling; van Duijn, Sava, Elena M.; Matsko, Dmitry E.; Semiglazov, Vladimir Cornelia M.; Kaprio, Jaakko; Cormand, Bru; Wessman, F.; Fichtner, Iduna; Larionov, Alexey A.; Kuznetsov, Maija; Frants, Rune R.; Meitinger, Thomas; Mueller- Sergey G.; Antoniou, Antonis C.; Imyanitov, Evgeny N. In: Myhsok, Bertram; Zwart, John-Anker; Färkkilä, Markus; International Journal of Cancer Research, Vol. 130, No. Macaya, Alfons; Ferrari, Michel D.; Kubisch, Christian; 12, 2012, p. 2867-2873. Palotie, Aarno; Dichgans, Martin; van den Maagdenberg, Arn M. J. M.; Int Headache Genetics Consortium. In: 98. High prevalence and breast cancer predisposing Nature Genetics, Vol. 44, No. 7, 2012, p. 777-U205. role of the BLM c.1642 C>T (Q548X) mutation in Russia. / Sokolenko, Anna; Iyevleva, 93. Genome-wide association study does not Aglaya; Preobrazhenskaya, Elena; Mitiushkina, Nathalia; reveal major genetic determinants for anti- Abysheva, Svetlana; Suspitsin, Evgeny; Kuligina, cytomegalovirus antibody response. / Kuparinen, Ekatherina; Gorodnova, Tatiana; Pfeifer, Werner; T.; Seppälä, I.; Jylhava, J.; Marttila, S.; Aittoniemi, J.; Togo, Alexandr; Turkevich, Elena; Ivantsov, Alexandr; Kettunen, J.; Viikari, J.; Kahonen, M.; Raitakari, O.; Voskresenskiy, Dmitry; Dolmatov, Georgy ; Bit-Sava, Lehtimäki, T.; Hurme, M. In: Genes and Immunity, Vol. 13, Elena; Matsko, Dmitry; Semiglazov, Vladimir; Fichtner, No. 2, 2012, p. 184-190. Iduna; Larionov, Alexey; Kuznetsov, Sergey; Antoniou, 94. Genome-wide association study identifies multiple Antonis; Imyanitov, Evgeny. In: International Journal of loci influencing human serum metabolite levels. / Cancer, Vol. 130, No. 12, 2012, p. 2867-2873.

78 • FIMM 99. High-Throughput Transcriptomic and RNAi Analysis Pedersen, Nancy L.; Borecki, Ingrid B.; Province, Michael Identifies AIM1, ERGIC1, TMED3 and TPX2 as A.; Balkau, Beverley; Froguel, Philippe; Shuldiner, Alan R.; Potential Drug Targets in Prostate Cancer. / Vainio, Palmer, Lyle J.; Wareham, Nick; Meneton, Pierre; Johnson, Paula; Mpindi, John Patrick; Kohonen, Pekka; Fey, Toby; Pankow, James S.; Karasik, David; Meigs, James Vidal; Mirtti, Tuomas; Alanen, Kalle A.; Perala, Merja; B.; Kiel, Douglas P.; Florez, Jose C.; ASCOT Investigators, Kallioniemi, Olli; Iljin, Kristiina. In: PLoS One, Vol. 7, No. DIAGRAM Consortium, MuTHER Consortium, MAGIC 6, 2012, p. Article Number: e398013. Investigators, GEFOS Consortium. In: Diabetes, Vol. 61, No. 8, 2012, p. 2176-2186. 100. High-resolution SNP array analysis of patients with developmental disorder and normal array CGH 106. Improved Statistical Modeling of Tumor Growth and results. / Siggberg, Linda; Ala-Mello, Sirpa; Linnankivi, Treatment Effect in Preclinical Animal Studies with Tarja; Avela, Kristiina; Scheinin, Ilari; Kristiansson, Kati; Highly Heterogeneous Responses In Vivo. / Laajala, Lahermo, Päivi; Hietala, Marja; Metsähonkala, Eeva- Teemu D.; Corander, Jukka; Saarinen, Niina M.; Makela, Liisa; Kuusinen, Esa; Laaksonen, Maarit; Saarela, Janna; Katja; Savolainen, Saija; Suominen, Mari I.; Alhoniemi, Knuutila, Sakari. In: BMC Medical Genetics, Vol. 13, No. Esa; Makela, Sari; Poutanen, Matti; Aittokallio, Tero. In: Article Number: 84, 2012. Clinical Cancer Research, Vol. 18, No. 16, 2012, p. 4385- 4396. 101. Hippocampal morphology in lithium and non- lithium-treated bipolar I disorder patients, non- 107. Increased Genetic Vulnerability to Smoking at bipolar co-twins, and control twins. / van Erp, Theo CHRNA5 in Early-Onset Smokers. / Hartz, Sarah G. M.; Thompson, Paul M.; Kieseppä, Tuula; Bearden, M.; Short, Susan E.; Saccone, Nancy L.; Culverhouse, Carrie E.; Marino, Alexandria C.; Hoftman, Gil D.; Haukka, Robert; Chen, LiShiun; Schwantes-An, Tae-Hwi; Coon, Jari; Partonen, Timo; Huttunen, Matti; Kaprio, Jaakko; Hilary; Han, Younghun; Stephens, Sarah H.; Sun, Lönnqvist, Jouko; Poutanen, Veli-Pekka; Toga, Arthur W.; Juzhong; Chen, Xiangning; Ducci, Francesca; Dueker, Cannon, Tyrone D. In: Human Brain Mapping, Vol. 33, No. Nicole; Franceschini, Nora; Frank, Josef; Geller, Frank; 3, 2012, p. 501-510. Guobjartsson, Daniel; Hansel, Nadia N.; Jiang, Chenhui; Keskitalo-Vuokko, Kaisu; Liu, Zhen; Lyytikainen, Leo- 102. Homologous recombination repairs secondary Pekka; Michel, Martha; Rawal, Rajesh; Hum, Sc; replication induced DNA double-strand breaks after Rosenberger, Albert; Scheet, Paul; Shaffer, John R.; ionizing radiation. / Petra P Groth, Manuel Luís ML Teumer, Alexander; Thompson, John R.; Vink, Jacqueline Orta, Ingegerd I Elvers, Muntasir Mamun MM Majumder, M.; Vogelzangs, Nicole; Wenzlaff, Angela S.; Wheeler, Anne A Lagerqvist, Thomas T Helleday. In: Nucleic Acids William; Xiao, Xiangjun; Yang, Bao-Zhu; Aggen, Steven Research, Vol. 40, No. 14, 2012, p. 6585-94. H.; Balmforth, Anthony J.; Baumeister, Sebastian E.; Beaty, Terri; Bennett, Siiri; Bergen, Andrew W.; Boyd, 103. Identification of MicroRNAs InhibitingTGF-beta- Heather A.; Broms, Ulla; Campbell, Harry; Chatterjee, Induced IL-11 Production in Bone Metastatic Breast Nilanjan; Chen, Jingchun; Cheng, Yu-Ching; Cichon, Cancer Cells. / Pollari, Sirkku; Leivonen, Suvi-Katri; Perala, Sven; Couper, David; Cucca, Francesco; Dick, Danielle Merja; Fey, Vidal; Kakonen, Sanna-Maria; Kallioniemi, M.; Foroud, Tatiana; Furberg, Helena; Giegling, Ina; Gu, Olli. In: PLoS One, Vol. 7, No. 5, 2012, p. Article Number: Fangyi; Hall, Alistair S.; Hällfors, Jenni Katariina; Han, e37361. Shizhong; Hartmann, Annette M.; Hayward, Caroline; 104. Identification of tumor epithelium and stroma in Heikkila, Kauko; Hewitt, John K.; Hottenga, Jouke Jan; tissue microarrays using texture analysis. / Linder, Jensen, Majken K.; Jousilahti, Pekka; Kaakinen, Marika; Nina; Konsti, Juho; Turkki, Riku; Rahtu, Esa; Lundin, Kittner, Steven J.; Konte, Bettina; Korhonen, Tellervo; Mikael; Nordling, Finn Stig Arnold; Haglund, Caj; Ahonen, Landi, Maria-Teresa; Laatikainen, Tiina; Leppert, Mark; Timo; Pietikainen, Matti; Lundin, Johan. In: Diagnostic Levy, Steven M.; Mathias, Rasika A.; McNeil, Daniel Pathology, Vol. 7, 2012, p. Article Number 22. W.; Medland, Sarah E.; Montgomery, Grant W.; Muley, Thomas; Murray, Tanda; Nauck, Matthias; North, Kari; 105. Impact of Common Variation in Bone-Related Genes Pergadia, Michele; Polasek, Ozren; Ramos, Erin M.; on Type 2 Diabetes and Related Traits. / Billings, Ripatti, Samuli; Risch, Angela; Ruczinski, Ingo; Rudan, Liana K.; Hsu, Yi-Hsiang; Ackerman, Rachel J.; Dupuis, Igor; Salomaa, Veikko; Schlessinger, David; Styrkarsdottir, Josee; Voight, Benjamin F.; Rasmussen-Torvik, Laura Unnur; Terracciano, Antonio; Uda, Manuela; Willemsen, J.; Hercberg, Serge; Lathrop, Mark; Barnes, Daniel; Gonneke; Wu, Xifeng; Abecasis, Goncalo; Barnes, Langenberg, Claudia; Hui, Jennie; Fu, Mao; Bouatia-Naji, Kathleen; Bickeboeller, Heike; Boerwinkle, Eric; Nabila; Lecoeur, Cecile; An, Ping; Magnusson, Patrik Boomsma, Dorret I.; Caporaso, Neil; Duan, Jubao; K.; Surakka, Ida Liisa; Ripatti, Samuli; Christiansen, Edenberg, Howard J.; Francks, Clyde; Gejman, Pablo Lene; Dalgard, Christine; Folkersen, Lasse; Grundberg, V.; Gelernter, Joel; Grabe, Hans Joergen; Hops, Hyman; Elin; Eriksson, Per; Kaprio, Jaakko; Kyvik, Kirsten Ohm; Jarvelin, Marjo-Riitta; Viikari, Jorma; Kahonen, Mika;

FIMM • 79 Kendler, Kenneth S.; Lehtimaki, Terho; Levinson, Douglas Chasman, Daniel I.; He, Chunyan; Mangino, Massimo; F.; Marazita, Mary L.; Marchini, Jonathan; Melbye, Sulem, Patrick; Barbalic, Maja; Broer, Linda; Byrne, Mads; Mitchell, Braxton D.; Murray, Jeffrey C.; Nothen, Enda M.; Ernst, Florian; Esko, Tonu; Franceschini, Markus M.; Penninx, Brenda W.; Raitakari, Olli; Rietschel, Nora; Gudbjartsson, Daniel F.; Hottenga, Jouke-Jan; Marcella; Rujescu, Dan; Samani, Nilesh J.; Sanders, Alan Kraft, Peter; McArdle, Patrick F.; Porcu, Eleonora; Shin, R.; Schwartz, Ann G.; Shete, Sanjay; Shi, Jianxin; Spitz, So-Youn; Smith, Albert V.; van Wingerden, Sophie; Margaret; Stefansson, Kari; Swan, Gary E.; Thorgeirsson, Zhai, Guangju; Zhuang, Wei V.; Albrecht, Eva; Alizadeh, Thorgeir; Volzke, Henry; Wei, Qingyi; Wichmann, H. Behrooz Z.; Aspelund, Thor; Bandinelli, Stefania; Lauc, -Erich; Amos, Christopher I.; Breslau, Naomi; Cannon, Lovorka Barac; Beckmann, Jacques S.; Boban, Mladen; Dale S.; Ehringer, Marissa; Grucza, Richard; Hatsukami, Boerwinkle, Eric; Broekmans, Frank J.; Burri, Andrea; Dorothy; Heath, Andrew; Johnson, Eric O.; Kaprio, Campbell, Harry; Chanock, Stephen J.; Chen, Constance; Jaakko; Madden, Pamela; Martin, Nicholas G.; Stevens, Cornelis, Marilyn C.; Corre, Tanguy; Coviello, Andrea D.; Victoria L.; Stitzel, Jerry A.; Weiss, Robert B.; Kraft, Peter; d’Adamo, Pio; Davies, Gail; de Faire, Ulf; de Geus, Eco Bierut, Laura J. In: Archives of General Psychiatry, Vol. 69, J. C.; Deary, Ian J.; Dedoussis, George V. Z.; Deloukas, No. 8, 2012, p. 854-861. Panagiotis; Ebrahim, Shah; Eiriksdottir, Gudny; Emilsson, Valur; Eriksson, Johan G.; Fauser, Bart C. J. M.; Ferreli, 108. Integrative genomic, transcriptomic, and RNAi Liana; Ferrucci, Luigi; Fischer, Krista; Folsom, Aaron R.; analysis indicates a potential oncogenic role for Garcia, Melissa E.; Gasparini, Paolo; Gieger, Christian; FAM110B in castration-resistant prostate cancer. Glazer, Nicole; Grobbee, Diederick E.; Hall, Per; Haller, / Vainio, Paula; Wolf, Maija; Edgren, Henrik; He, Tao; Toomas; Hankinson, Susan E.; Hass, Merli; Hayward, Kohonen, Pekka; Mpindi, John Patrick; Smit, Frank; Caroline; Heath, Andrew C.; Hofman, Albert; Ingelsson, Verhaegh, Gerald; Schalken, Jack; Perala, Merja; Iljin, Erik; Janssens, A. Cecile J. W.; Johnson, Andrew D.; Kristiina; Kallioniemi, Olli. In: Prostate, Vol. 72, No. 7, Karasik, David; Kardia, Sharon L. R.; Keyzer, Jules; Kiel, 2012, p. 789-802. Douglas P.; Kolcic, Ivana; Kutalik, Zoltan; Lahti, Jari; Lai, 109. Interaction with ErbB4 Promotes Hypoxia-inducible Sandra; Laisk, Triin; Laven, Joop S. E.; Lawlor, Debbie Factor-1 alpha Signaling. / Paatero, Ilkka; Jokilammi, A.; Liu, Jianjun; Lopez, Lorna M.; Louwers, Yvonne V.; Anne; Heikkinen, Pekka T.; Iljin, Kristiina; Kallioniemi, Magnusson, Patrik K. E.; Marongiu, Mara; Martin, Olli-Pekka; Jones, Frank E.; Jaakkola, Panu M.; Elenius, Nicholas G.; Klaric, Irena Martinovic; Masciullo, Corrado; Klaus. In: Journal of Biological Chemistry, Vol. 287, No. McKnight, Barbara; Medland, Sarah E.; Melzer, David; 13, 2012, p. 9659-9671. Mooser, Vincent; Navarro, Pau; Newman, Anne B.; Nyholt, Dale R.; Onland-Moret, N. Charlotte; Palotie, 110. Intracranial Aneurysm Risk Locus 5q23.2 Is Aarno; Pare, Guillaume; Parker, Alex N.; Pedersen, Nancy Associated with Elevated Systolic Blood Pressure. L.; Peeters, Petra H. M.; Pistis, Giorgio; Plump, Andrew / Gaal, Emilia Ilona; Salo, Perttu; Kristiansson, Kati; S.; Polasek, Ozren; Pop, Victor J. M.; Psaty, Bruce M.; Rehnstrom, Karola; Kettunen, Johannes; Sarin, Antti- Räikkönen, Katri; Rehnberg, Emil; Rotter, Jerome I.; Pekka; Niemela, Mika; Jula, Antti; Raitakari, Olli T.; Rudan, Igor; Sala, Cinzia; Salumets, Andres; Scuteri, Lehtimaki, Terho; Eriksson, Johan G.; Widen, Elisabeth; Angelo; Singleton, Andrew; Smith, Jennifer A.; Snieder, Guenel, Murat; Kurki, Mitja; Fraunberg, Mikael von Und Harold; Soranzo, Nicole; Stacey, Simon N.; Starr, John Zu; Jaaskelainen, Juha E.; Hernesniemi, Juha; Jarvelin, M.; Stathopoulou, Maria G.; Stirrups, Kathleen; Stolk, Marjo-Riitta; Pouta, Anneli; Newton-Cheh, Christopher; Ronald P.; Styrkarsdottir, Unnur; Sun, Yan V.; Tenesa, Salomaa, Veikko; Palotie, Aarno; Perola, Markus; Albert; Thorand, Barbara; Toniolo, Daniela; Tryggvadottir, ICBP-GWAS. In: PLoS Genetics, Vol. 8, No. 3, 2012, p. Laufey; Tsui, Kim; Ulivi, Sheila; van Dam, Rob M.; van der e1002563. Schouw, Yvonne T.; van Gils, Carla H.; van Nierop, Peter; Vink, Jacqueline M.; Visscher, Peter M.; Voorhuis, Marlies; 111. Lysophosphatidic acid and sphingosine-1-phosphate Waeber, Gerard; Wallaschofski, Henri; Wichmann, H. promote morphogenesis and block invasion Erich; Widen, Elisabeth; Wijnands-van Gent, Colette J. M.; of prostate cancer cells in three-dimensional Willemsen, Gonneke; Wilson, James F.; Wolffenbuttel, organotypic models. / Härmä, Ville; Knuuttila, Matias; Bruce H. R.; Wright, Alan F.; Yerges-Armstrong, Laura Virtanen, Johannes; Mirtti, Tuomas; Kohonen, Pekka; M.; Zemunik, Tatijana; Zgaga, Lina; Zillikens, M. Carola; Kovanen, Panu Esko; Happonen, A; Kaewphan, S; Zygmunt, Marek; Arnold, Alice M.; Boomsma, Dorret Ahonen, I; Kallioniemi, Olli; Nees, Matthias; Grafström, I.; Buring, Julie E.; Crisponi, Laura; Demerath, Ellen W.; R; Lötjönen, J. In: Oncogene, Vol. 31, No. 16, 2012, p. Gudnason, Vilmundur; Harris, Tamara B.; Hu, Frank B.; 2075-2089. Hunter, David J.; Launer, Lenore J.; Metspalu, Andres; 112. Meta-analyses identify 13 loci associated with Montgomery, Grant W.; Oostra, Ben A.; Ridker, Paul age at menopause and highlight DNA repair and M.; Sanna, Serena; Schlessinger, David; Spector, Tim D.; immune pathways. / Stolk, Lisette; Perry, John R. B.; Stefansson, Kari; Streeten, Elizabeth A.; Thorsteinsdottir,

80 • FIMM Unnur; Uda, Manuela; Uitterlinden, Andre G.; van Duijn, M.; Jalanko, Anu. In: Cellular and Molecular Life Sciences, Cornelia M.; Voelzke, Henry; Murray, Anna; Murabito, Vol. 69, No. 12, 2012, p. 2075-2089. Joanne M.; Visser, Jenny A.; Lunetta, Kathryn L.; LifeLines 119. New susceptibility loci associated with kidney Cohort Study. In: Nature Genetics, Vol. 44, 2012, p. 260- disease in type 1 diabetes. / Sandholm, Niina; U55. Salem, Rany M.; McKnight, Amy Jayne; Brennan, Eoin 113. Meta-analysis of genome-wide association P.; Forsblom, Carol; Isakova, Tamara; McKay, Gareth studies for personality. / de Moor, M. H. M.; Costa, J.; Williams, Winfred W.; Sadlier, Denise M.; Mäkinen, P. T.; Terracciano, A.; Krueger, R. F.; de Geus, E. J. C.; Ville-Petteri; Swan, Elizabeth J. ; Palmer, Cameron; Toshiko, T.; Penninx, B. W. J. H.; Esko, T.; Madden, P. Boright, Andrew P.; Ahlqvist, Emma; Deshmukh, Harshal A. F.; Derringer, J.; Amin, N.; Willemsen, G.; Hottenga, A.; Keller, Benjamin J.; Huang, Huateng; Ahola, Aila; J-J; Distel, M. A.; Uda, M.; Sanna, S.; Spinhoven, P.; Fagerholm, Emma; Gordin, Ted Daniel; Harjutsalo, Hartman, C. A.; Sullivan, P.; Realo, A.; Allik, J.; Heath, A. Valma; He, Bing; Heikkilä, Outi; Hietala, Kustaa ; Kytö, C.; Pergadia, M. L.; Agrawal, A.; Lin, P.; Grucza, R.; Nutile, Janne; Lahermo, Päivi; Lehto, Markku; Lithovius, Raija; T.; Ciullo, M.; Rujescu, D.; Giegling, I.; Konte, B.; Widen, Österholm, Anne-May; Parkkonen, Maija; Pitkäniemi, E.; Cousminer, D. L.; Eriksson, J. G.; Palotie, A.; Palotie, Janne Mikael; Rosengård-Bärlund, Milla; Saraheimo, Leena; Luciano, M.; Tenesa, A.; Davies, G.; Lopez, L. M.; Markku; Sarti, Cinzia; Söderlun, Jenny; Soro-Paavonen, Hansell, N. K.; Medland, S. E.; Ferrucci, L.; Schlessinger, Aino; Syreeni, Anna; Thorn, Lena; Tikkanen, Heikki Olavi; D.; Montgomery, G. W.; Wright, M. J.; Aulchenko, Y. S.; Tolonen, Nina Emilia; Tryggvason, Karl; Tuomilehto, Janssens, A. C. J. W.; Oostra, B. A.; Metspalu, A.; Abecasis, Jaakko; Waden, Johan; Gill, Geoffrey V.; Prior, Sarah; G. R.; Deary, I. J.; Räikkönen, Katri; Bierut, L. J.; Martin, Guiducci, Candace; Mirel, Daniel B.; Taylor, Andrew; N. G.; van Duijn, C. M.; Boomsma, D. I. In: Molecular Hosseini, S. Mohsen; EDIC Research Group, DCCT/; Psychiatry, Vol. 17, No. 3, 2012, p. 337-349. Parving, Hans-Henrik; Rossing, Peter; Tarnow, Lise; Ladenvall, Claes; Alhenc-Gelas, Francois; Lefebvre, Pierre; 114. Metabolic Signatures of Insulin Resistance in Rigalleau, Vincent; Roussel, Ronan; Tregouet, David- 7,098 Young Adults. / Wurtz, Peter; Makinen, Ville- Alexandre; Maestroni, Anna; Falhammar, Henrik; Gu, Petteri; Soininen, Pasi; Kangas, Antti J.; Tukiainen, Taru; Tianwei; Möllsten, Anna; Cimponeriu, Danut; Ioana, Kettunen, Johannes; Savolainen, Markku J.; Tammelin, Mihai; Mota, Maria; Mota, Eugen; Serafinceanu, Cristian; Tuija; Viikari, Jorma S.; Ronnemaa, Tapani; Kahonen, Stavarachi, Monica; Hanson, Robert L.; Nelson, Robert Mika; Lehtimaki, Terho; Ripatti, Samuli; Raitakari, Olli T.; G.; Kretzler, Matthias; Colhoun, Helen M.; Panduru, Jarvelin, Marjo-Riitta; Ala-Korpela, Mika. In: Diabetes, Nicolae Mircea; Gu, Harvest F.; Brismar, Kerstin; Zerbini, Vol. 61, No. 6, 2012, p. 1372-1380. Gianpaolo; Hadjadj, Samy; Marre, Michel; Groop, Leif; Lajer, Maria; Bull, Shelley B.; Waggott, Daryl; Paterson, 115. Mining high-throughput screens for cancer drug Andrew D.; Savage, David A.; Bain, Stephen C.; Martin, targets-lessons from yeast chemical-genomic Finian; Hirschhorn, Joel N.; Godson, Catherine; Florez, profiling and synthetic lethality. / Heiskanen, Marja Jose C.; Groop, Per Henrik; Maxwell, Alexander P. In: PLoS A.; Aittokallio, Tero. In: Wiley interdisciplinary reviews. Genetics, Vol. 8, No. 9, 2012, p. e1002921. Data mining and knowledge discovery, Vol. 2, No. 3, 2012, p. 263-272. 120. No Association of nineteen COX-2 gene variants to preclinical markers of atherosclerosis The 116. Multiple heat pulses during PCR extension enables Cardiovascular Risk in Young Finns Study. / amplification of GC-rich sequences and educesr Lahteela, Kati; Kunnas, Tarja; Lyytikainen, Leo-Pekka; amplification bias.. / Orpana, Arto K.; Ho, Tho H.; Mononen, Nina; Taittonen, Leena; Laitinen, Tomi; Stenman, Jakob. In: Analytical Chemistry, Vol. 84, No. 4, Kettunen, Johannes; Juonala, Markus; Hutri-Kahonen, 2012, p. 2081-2087. Nina; Kahonen, Mika; Viikari, Jorma S.; Raitakari, Olli T.; Lehtimaki, Terho; Nikkari, Seppo T. In: BMC Medical 117. Mutations of complement lectin pathway genes Genetics, Vol. 13, 2012, p. Article Number: 32. MBL2 and MASP2 associated with placental malaria. / Holmberg, Ville; Onkamo, Paivi; Lahtela, Laura Elisa; 121. Noise sensitivity and multiple chemical sensitivity Lahermo, Paivi; Bedu-Addo, George; Mockenhaupt, Frank scales: Properties in a population based P.; Meri, Seppo. In: Malaria Journal, Vol. 11, No. art. no 61, epidemiological study. / Heinonen-Guzejev, Marja; 2012, p. -. Koskenvuo, Markku; Mussalo-Rauhamaa, Helena; Vuorinen, Heikki S; Heikkilä, Kauko Veli; Kaprio, Jaakko. 118. Neuronal ceroid lipofuscinosis protein CLN3 In: Noise & Health, Vol. 14, No. 60, 2012, p. 215-223. interacts with motor proteins and modifies location of late endosomal compartments. / Uusi-Rauva, 122. Novel Loci for Adiponectin Levels and Their Influence Kristiina; Kyttälä, Aija; van der Kant, Rik; Vesa, Jouni; on Type 2 Diabetes and Metabolic Traits : A Multi- Tanhuanpaa, Kimmo; Neefjes, Jacques; Olkkonen, Vesa Ethnic Meta-Analysis of 45,891 Individuals. / Dastani,

FIMM • 81 Zari; Hivert, Marie-France; Timpson, Nicholas; Perry, 125. On the Validity of the Likelihood Ratio Test and John R. B.; Yuan, Xin; Scott, Robert A.; Henneman, Peter; Consistency of Resulting Parameter Estimates in Heid, Iris M.; Kizer, Jorge R.; Lyytikainen, Leo-Pekka; Joint Linkage and Linkage Disequilibrium Analysis Fuchsberger, Christian; Tanaka, Toshiko; Morris, Andrew under Improperly Specified Parametric Models. / P.; Small, Kerrin; Isaacs, Aaron; Beekman, Marian; Hiekkalinna, Tero; Goering, Harald H. H.; Terwilliger, Coassin, Stefan; Lohman, Kurt; Qi, Lu; Kanoni, Stavroula; Joseph D. In: Annals of Human Genetics, Vol. 76, 2012, p. Pankow, James S.; Uh, Hae-Won; Wu, Ying; Bidulescu, 63-73. Aurelian; Rasmussen-Torvik, Laura J.; Greenwood, Celia M. T.; Ladouceur, Martin; Grimsby, Jonna; Manning, 126. On the statistical properties of family-based Alisa K.; Liu, Ching-Ti; Kooner, Jaspal; Mooser, Vincent E.; association tests in datasets containing both Vollenweider, Peter; Kapur, Karen A.; Chambers, John; pedigrees and unrelated case-control samples : Wareham, Nicholas J.; Langenberg, Claudia; Frants, Comparison of family-based association tests. / Rune; Willems-vanDijk, Ko; Oostra, Ben A.; Willems, Sara Hiekkalinna, Tero; Goering, Harald H. H.; Lambert, Brian; M.; Lamina, Claudia; Winkler, Thomas W.; Psaty, Bruce Weiss, Kenneth M.; Norrgrann, Petri; Schaeffer, Alejandro M.; Tracy, Russell P.; Brody, Jennifer; Chen, Ida; Viikari, A.; Terwilliger, Joseph D. In: European Journal of Human Jorma; Kahonen, Mika; Pramstaller, Peter P.; Evans, Genetics, Vol. 20, No. 2, 2012, p. 217-223. David M.; St Pourcain, Beate; Sattar, Naveed; Wood, 127. On the superior power of likelihood-based linkage Andrew R.; Bandinelli, Stefania; Carlson, Olga D.; Egan, disequilibrium mapping in large multiplex families Josephine M.; Bohringer, Stefan; van Heemst, Diana; compared to population based case-control designs. Kedenko, Lyudmyla; Kristiansson, Kati; Nuotio, Marja- / Hiekkalinna, Tero. Helsinki : Terveyden ja hyvinvoinnin Liisa; Loo, Britt-Marie; Harris, Tamara; Garcia, Melissa; laitos, 2012. 107 p. (Research / National Institute for Kanaya, Alka; Haun, Margot; Klopp, Norman; Wichmann, Health and Welfare; 88). H. -Erich; Deloukas, Panos; Katsareli, Efi; Couper, David J.; Duncan, Bruce B.; Kloppenburg, Margreet; Adair, 128. Optimized detection of transcription factor- Linda S.; Borja, Judith B.; Wilson, James G.; Musani, binding sites in ChIP-seq experiments. / Elo, Laura Solomon; Guo, Xiuqing; Johnson, Toby; Semple, Robert; L.; Kallio, Aleksi; Laajala, Teemu D.; Hawkins, R. David; Teslovich, Tanya M.; Allison, Matthew A.; Redline, Susan; Korpelainen, Eija; Aittokallio, Tero. In: Nucleic Acids Buxbaum, Sarah G.; Mohlke, Karen L.; Meulenbelt, Ingrid; Research, Vol. 40, No. 1, 2012, p. e1. Ballantyne, Christie M.; Dedoussis, George V.; Hu, Frank B.; Liu, Yongmei; Paulweber, Bernhard; Spector, Timothy 129. Phosphoprotein profiling predicts response to D.; Slagboom, P. Eline; Ferrucci, Luigi; Jula, Antti; Perola, tyrosine kinase inhibitor therapy in chronic myeloid Markus; Raitakari, Olli; Florez, Jose C.; Salomaa, Veikko; leukemia patients. / Jalkanen, Sari E.; Lahesmaa- Eriksson, Johan G.; Frayling, Timothy M.; Hicks, Andrew Korpinen, Anna-Maria Kristiina; Heckman, Caroline; A.; Lehtimaki, Terho; Smith, George Davey; Siscovick, Rantanen, Ville; Porkka, Kimmo; Hautaniemi, Sampsa; David S.; Kronenberg, Florian; van Duijn, Cornelia; Loos, Mustjoki, Satu. In: Experimental Hematology, Vol. 40, Ruth J. F.; Waterworth, Dawn M.; Meigs, James B.; No. 9, 2012, p. 704-714. Dupuis, Josee; Richards, J. Brent; GLGC Investigators, DIAGRAM Consortium, MAGIC Consortium, MuTHER 130. Plasma HDL cholesterol and risk of myocardial Consortium ; Ripatti, Samuli; Kaprio, Jaakko. In: PLoS infarction: a mendelian randomisation study. / Genetics, Vol. 8, No. 3, 2012, p. e1002607. Voight, Benjamin F.; Peloso, Gina M.; Orho-Melander, Marju; Frikke-Schmidt, Ruth; Barbalic, Maja; Jensen, 123. Novel mutations consolidate KCTD7 as a progressive Majken K.; Hindy, George; Holm, Hilma; Ding, Eric L.; myoclonus epilepsy gene. / Kousi, Maria; Anttila, Johnson, Toby; Schunkert, Heribert; Samani, Nilesh J.; Verneri; Schulz, Angela; Calafato, Stella; Jakkula, Eveliina; Clarke, Robert; Hopewell, Jemma C.; Thompson, John Riesch, Erik; Myllykangas, Liisa; Kalimo, Hannu; Topcu, F.; Li, Mingyao; Thorleifsson, Gudmar; Newton-Cheh, Meral; Gokben, Sarenur; Alehan, Fusun; Lemke, Johannes Christopher; Musunuru, Kiran; Pirruccello, James P.; R.; Alber, Michael; Palotie, Aarno; Kopra, Outi; Lehesjoki, Saleheen, Danish; Chen, Li; Stewart, Alexandre F. R.; Anna-Elina. In: Journal of Medical Genetics, Vol. 49, No. Schillert, Arne; Thorsteinsdottir, Unnur; Thorgeirsson, 6, 2012, p. 391-399. Gudmundur; Anand, Sonia; Engert, James C.; Morgan, Thomas; Spertus, John; Stoll, Monika; Berger, Klaus; 124. Obesity-Related Derangements of Coagulation Martinelli, Nicola; Girelli, Domenico; McKeown, Pascal and Fibrinolysis : A Study of Obesity-Discordant P.; Patterson, Christopher C.; Epstein, Stephen E.; Monozygotic Twin pairs. / Kaye, Sanna M.; Pietiläinen, Devaney, Joseph; Burnett, Mary-Susan; Mooser, Vincent; Kirsi Hannele; Kotronen, Anna; Joutsi-Korhonen, Lotta; Ripatti, Samuli; Surakka, Ida; Nieminen, Markku S.; Kaprio, Jaakko; Yki-Järvinen, Hannele; Silveira, Angela; Sinisalo, Juha-Pekka; Lokki, Marja-Liisa; Perola, Markus; Hamsten, Anders; Lassila, Riitta; Rissanen, Aila. In: Havulinna, Aki; de Faire, Ulf; Gigante, Bruna; Ingelsson, Obesity, Vol. 20, No. 1, 2012, p. 88-94. Erik; Zeller, Tanja; Wild, Philipp; de Bakker, Paul I. W.;

82 • FIMM Klungel, Olaf H.; Maitland-van der Zee, Anke-Hilse; cohort. / Nyman, Emma S.; Loukola, Anu; Varilo, Teppo; Peters, Bas J. M.; de Boer, Anthonius; Grobbee, Diederick Taanila, Anja; Hurtig, Tuula; Moilanen, Irma; Loo, Sandra; E.; Kamphuisen, Pieter W.; Deneer, Vera H. M.; Elbers, McGough, James J.; Jarvelin, Marjo-Riitta; Smalley, Susan Clara C.; Onland-Moret, N. Charlotte; Hofker, Marten L.; Nelson, Stanley F.; Palotie, Leena. In: Psychiatric H.; Wijmenga, Cisca; Verschuren, W. M. Monique; Boer, Genetics, Vol. 22, No. 4, 2012, p. 197-201. Jolanda M. A.; van der Schouw, Yvonne T.; Rasheed, Asif; Frossard, Philippe; Demissie, Serkalem; Willer, 136. Shared loci for migraine and epilepsy on Cristen; Do, Ron; Ordovas, Jose M.; Abecasis, Goncalo chromosomes 14q12-q23 and 12q24.2-q24.3. / Polvi, R.; Boehnke, Michael; Mohlke, Karen L.; Daly, Mark J.; Anne; Siren, A.; Kallela, Kaarlo Mikko Juhani; Rantala, H.; Guiducci, Candace; Burtt, Noel P.; Surti, Aarti; Gonzalez, Artto, Ville; Sobel, E.; Palotie, Aarno; Lehesjoki, Anna- Elena; Purcell, Shaun; Gabriel, Stacey; Marrugat, Jaume; Elina; Wessman, Maija. In: Neurology, Vol. 78, No. 3, Peden, John; Erdmann, Jeanette; Diemert, Patrick; 2012, p. 202 - 209. Willenborg, Christina; Koenig, Inke R.; Fischer, Marcus; 137. Somatic STAT3 Mutations in Large Granular Hengstenberg, Christian; Ziegler, Andreas; Buysschaert, Lymphocytic Leukemia. / Koskela, Hanna L. M.; Ian; Lambrechts, Diether; Van de Werf, Frans; Fox, Eldfors, Samuli; Ellonen, Pekka; van Adrichem, Arjan J.; Keith A.; El Mokhtari, Nour Eddine; Rubin, Diana; Kuusanmäki, Heikki; Andersson, Emma I.; Lagstrom, Schrezenmeir, Juergen; Schreiber, Stefan; Schaefer, Arne; Sonja; Clemente, Michael J.; Olson, Thomas; Jalkanen, Danesh, John; Blankenberg, Stefan; Roberts, Robert; Sari E.; Majumder, Muntasir Mamun; Almusa, Henrikki; McPherson, Ruth; Watkins, Hugh; Hall, Alistair S.; Edgren, Henrik; Lepisto, Maija; Mattila, Pirkko; Guinta, Overvad, Kim; Rimm, Eric; Boerwinkle, Eric; Tybjaerg- Kathryn; Koistinen, Pirjo; Kuittinen, Taru; Penttinen, Hansen, Anne; Cupples, L. Adrienne; Reilly, Muredach Kati; Parsons, Alun; Knowles, Jonathan; Saarela, P.; Melander, Olle; Mannucci, Pier M.; Ardissino, Diego; Janna; Wennerberg, Krister; Kallioniemi, Olli; Porkka, Siscovick, David; Elosua, Roberto; Stefansson, Kari; Kimmo; Loughran, Thomas P.; Heckman, Caroline O’Donnell, Christopher J.; Salomaa, Veikko; Rader, Daniel A.; Maciejewski, Jaroslaw P.; Mustjoki, Satu. In: New J.; Palotie, Leena; Schwartz, Stephen M.; Altshuler, David; England Journal of Medicine, Vol. 366, No. 20, 2012, p. Kathiresan, Sekar. In: Lancet, Vol. 380, No. 9841, 2012, p. 1905-1913. 572-580. 138. Systematic knockdown of epigenetic enzymes 131. Pubertal Timing and Growth Influences identifies a novel histone demethylase PHF8 Cardiometabolic Risk Factors in Adult Males and overexpressed in prostate cancer with an impact Females. / Widen, Elisabeth; Silventoinen, Karri; Sovio, on cell proliferation, migration and invasion. / Ulla; Ripatti, Samuli; Cousminer, Diana L.; Hartikainen, Björkman, M; Östling, Päivi Kristina; Härmä, V; Virtanen, Anna-Liisa; Laitinen, Jaana; Pouta, Anneli; Kaprio, Jaakko; J; Mpindi, JP; Rantala, J; Mirtti, Tuomas; Vesterinen, Tiina; Jarvelin, Marjo-Riitta; Peltonen, Leena; Palotie, Aarno. Lundin, Mikael Edvard; Sankila, Anna Maaria; Rannikko, In: Diabetes Care, Vol. 35, No. 4, 2012, p. 850-856. Antti Sakari; Kaivanto, E; Kohonen, P; Kallioniemi, Olli- 132. Salinomycin inhibits prostate cancer growth and Pekka; Nees, M. In: Oncogene, Vol. 31, No. 29, 2012, p. migration via induction of oxidative stress. / Ketola, 3444-3456 . K.; Hilvo, M.; Hyotylainen, T.; Vuoristo, A.; Ruskeepaa, 139. TBX22 and Tongue-tie. / Klockars, Tuomas; Kyttänen, A-L; Oresic, M.; Kallioniemi, O.; Iljin, K. In: British Journal Suvi; Ellonen, Pekka. In: Cleft Palate - Craniofacial of Cancer, Vol. 106, No. 1, 2012, p. 99-106. Journal, Vol. 49, No. 3, 2012, p. 378-379. 133. Search for susceptibility genes in osteoarthritis. / 140. TRIB1 constitutes a molecular link between Näkki, Annu. Helsinki : National Institute for Health and regulation of sleep and lipid metabolism in humans. Welfare, 2012. 110 p. (Research / National Institute for / Ollila, Hanna Maria; Utge, S; Kronholm, E; van Health and Welfare; 77). Leeuwen, W; Silander, Kaisa; Partonen, T; Perola, Markus; 134. Sex differences in bladder cancer outcomes Kaprio, Jaakko; Salomaa, V; Sallinen, M; Härmä, M; among smokers with advanced bladder cancer. / Porkka-Heiskanen, Tarja; Paunio, Tiina. In: Translational Bostroem, Peter J.; Alkhateeb, Sultan; Trottier, Greg; Psychiatry, Vol. 2, No. 3, 2012, p. e97. Athanasopoulos, Paul Z.; Mirtti, Tuomas; Kortekangas, Hannes; Laato, Matti; van Rhijn, Bas; van der Kwast, 141. Technique for strand-specific gene-expression Theo; Fleshner, Neil E.; Jewett, Michael A.; Finelli, analysis and monitoring of primer-independent Antonio; Zlotta, Alexandre R. In: BJU International, Vol. cDNA synthesis in reverse transcription. / Feng, Lin; 109, No. 1, 2012, p. 70-76. Lintula, Susanna; Ho, Tho Huu; Anastasina, Maria; Paju, Annukka; Haglund, Caj; Stenman, Ulf Håkan; Hotakainen, 135. Sex-specific influence of DRD2 on ADHD-type Kristina; Orpana, Arto; Kainov, Denis; Stenman, Jakob. In: temperament in a large population-based birth BioTechniques, Vol. 52, No. 4, 2012, p. 263-270.

FIMM • 83 142. Temperament Clusters in a Normal Population: Pathways and Molecular Mediators in Metastasis : Implications for Health and Disease. / Wessman, Transcription Factors Stat5a/b and Stat3 in Prostate Jaana; Schonauer, Stefan; Miettunen, Jouko; Turunen, Cancer Growth and Metastases.. ed. / Alessandro Fatatis. Hannu; Parviainen, Pekka; Seppanen, Jouni K.; Congdon, Netherlands : Springer, 2012. p. 245-260. Eliza; Service, Susan; Koiranen, Markku; Ekelund, Jesper; Laitinen, Jaana; Taanila, Anja; Tammelin, Tuija; 146. Weight change and lipoprotein particle Hintsanen, Mirka; Pulkki-Raback, Laura; Keltikangas- concentration and particle size: A cohort study with Jarvinen, Liisa; Viikari, Jorma; Raitakari, Olli T.; Joukamaa, 6.5-year follow-up. / Mantyselka, Pekka; Kautiainen, Matti; Jarvelin, Marjo-Riitta; Freimer, Nelson; Palotie, Hannu; Saltevo, Juha; Würtz, Peter; Soininen, Pasi; Leena; Veijola, Juha; Mannila, Heikki; Paunio, Tiina. In: Kangas, Antti J.; Ala-Korpela, Mika; Vanhala, Mauno. In: PLoS One, Vol. 7, No. 7, 2012, p. Article Number: e33088. Atherosclerosis, Vol. 223, No. 1, 2012, p. 239-243.

143. The gene expression landscape of breast cancer is 147. Work-Related Exhaustion and Telomere Length: shaped by tumor protein p53 status and epithelial- A Population-Based Study. / Ahola, Kirsi; Siren, Ilari; mesenchymal transition. / Fredlund, Erik; Staaf, Johan; Kivimaki, Mika; Ripatti, Samuli; Aromaa, Arpo; Lönnqvist, Rantala, Juha K.; Kallioniemi, Olli; Borg, Ake; Ringner, Jouko; Hovatta, Iiris. In: PLoS One, Vol. 7, No. 7, 2012, p. Markus. In: Breast Cancer Research (Online Edition), Vol. Article Number: e40186. 14, No. 4, 2012, p. Article Number: R113. 148. c-Jun N-Terminal Kinase Phosphorylation of 144. The rocky road to personalized medicine: MARCKSL1 Determines Actin Stability and Migration computational and statistical challenges. / Corander, in Neurons and in Cancer Cells. / Bjorkblom, Benny; Jukka; Aittokallio, Tero; Ripatti, Samuli; Kaski, Samuel. Padzik, Artur; Mohammad, Hasan; Westerlund, Nina; In: Personalized Medicine, Vol. 9, No. 2, 2012, p. 109-114. Komulainen, Emilia; Hollos, Patrik; Parviainen, Lotta; Papageorgiou, Anastassios C.; Iljin, Kristiina; Kallioniemi, 145. Transcription Factors Stat5a/b and Stat3 in Prostate Olli; Kallajoki, Markku; Courtney, Michael J.; Magard, Cancer Growth and Metastases. / Mirtti, Tuomas; Mats; James, Peter; Coffey, Eleanor T. In: Molecular and Talati, Pooja; Nevalainen, Marja T. In: In: Signaling Cellular Biology, Vol. 32, No. 17, 2012, p. 3513-3526.

84 • FIMM FIMM collaborators and collaborating Year Prospective Study of Finnish Twins. / Ropponen, institutes Annina; Silventoinen, Karri; Svedberg, Pia; Alexanderson, Kristina; Huunan-Seppala, Antti; Koskenvuo, Karoliina; Koskenvuo, Markku; Kaprio, Jaakko. In: Journal of 1. Genetic Factors Account for Half of the Phenotypic Occupational and Environmental Medicine, Vol. 54, No. Variance in Liability to Sleep-Related Bruxism in 11, 11.2012, p. 1330-1336. Young Adults: A Nationwide Finnish Twin Cohort 9. Twins and the mystery of missing heritability: the Study. / Rintakoski, Katariina; Hublin, Christer; contribution of gene-environment interactions. / Lobbezoo, Frank; Rose, Richard J.; Kaprio, Jaakko. In: Kaprio, J. In: Journal of internal medicine, Vol. 272, No. 5, Twin Research and Human Genetics, Vol. 15, No. 6, 11.2012, p. 440-448. 12.2012, p. 714-719. 10. Mitochondrial phenylalanyl-tRNA synthetase 2. Hormone therapy is associated with better body mutations underlie fatal infantile Alpers composition and adipokine/glucose profiles: a encephalopathy. / Elo, Jenni M.; Yadavalli, Srujana S.; study with monozygotic co-twin control design. Euro, Liliya; Isohanni, Pirjo; Götz, Alexandra; Carroll, / Ahtiainen, Maarit; Alen, Markku; Pollanen, Eija; Christopher J.; Valanne, Leena; Alkuraya, Fowzan S.; Pulkkinen, Suvi; Ronkainen, Paula H. A.; Kujala, Urho M.; Uusimaa, Johanna; Paetau, Anders; Caruso, Eric M.; Kaprio, Jaakko; Sipila, Sarianna; Kovanen, Vuokko. In: Pihko, Helena; Ibba, Michael; Tyynismaa, Henna; Menopause, Vol. 19, No. 12, 12.2012, p. 1329-1335. Suomalainen, Anu. In: Human Molecular Genetics, Vol. 3. Mitä uutta tupakkariippuvuudesta ja sen hoidosta?. 21, No. 20, 15.10.2012, p. 4521-4529. / Kinnunen, Taru; Korhonen, Tellervo; Kaprio, Jaakko. 11. Angiopoietin-Like 4 Mediates PPAR Delta Effect on In: Suomen lääkärilehti, Vol. 67, No. 48, 30.11.2012, p. Lipoprotein Lipase-Dependent Fatty Acid Uptake 3559-3563. but Not on Beta-Oxidation in Myotubes. / Robciuc, 4. An Oncolytic Adenovirus Enhanced for Toll-like Marius Robert; Skrobuk, Paulina; Anisimov, Andrey; Receptor 9 Stimulation Increases Antitumor Immune Olkkonen, Vesa; Alitalo, Kari; Eckel, Robert; Koistinen, Responses and Tumor Clearance. / Cerullo, Vincenzo; Heikki Allan; Jauhiainen, Matti; Ehnholm, Christian. In: Diaconu, Iulia; Romano, Valentina; Hirvinen, Mari; Ugolini, PLoS One, Vol. 7, No. 10, 04.10.2012, p. e46212. Matteo; Escutenaire, Sophie; Sirkka-Liisa, Holm ; Kipar, 12. Capsid-Modified Adenoviral ectorsV for Improved Anja; Kanerva, Anna-Maija; Hemminki, Akseli. In: Molecular Muscle-Directed Gene Therapy. / Guse, Kilian; therapy, Vol. 20, No. 11, 01.11.2012, p. 2076-2086. Suzuki, Masataka; Sule, Gautam; Bertin, Terry K.; 5. Deficiency of the complex I of the mitochondrial Tyynismaa, Henna; Ahola-Erkkila, Sofia; Palmer, Donna; respiratory chain but improved adenylate control Suomalainen, Anu; Ng, Philip; Cerullo, Vincenzo; over succinate-dependent respiration are human Hemminki, Akseli; Lee, Brendan. In: Human Gene gastric cancer-specific phenomena. / Puurand, Therapy, Vol. 23, No. 10, 01.10.2012, p. 1065-1070. Marju; Peet, Nadezda; Piirsoo, Andres; Peetsalu, Margot; 13. Genome-wide association analysis of eating Soplepmann, Jaan; Sirotkina, Meeli; Peetsalu, Ants; disorder-related symptoms, behaviors, and Hemminki, Akseli; Seppet, Enn. In: Molecular and Cellular personality traits. / Boraska, Vesna; Davis, Oliver S. Biochemistry, Vol. 370, No. 1-2, 01.11.2012, p. 69-78. P.; Cherkas, Lynn F.; Helder, Sietske G.; Harris, Juliette; 6. Genetic and Environmental Influences on Chest Krug, Isabel; Pei-Chi Liao, Thomas; Treasure, Janet; Circumference during Infancy: A Longitudinal Ntalla, Ioanna; Karhunen, Leila; Keski-Rahkonen, Anna; Study of Japanese Twins. / Silventoinen, Karri; Kaprio, Christakopoulou, Danai; Raevuori, Anu; Shin, So-Youn; Jaakko; Dunkel, Leo; Yokoyama, Yoshie. In: Paediatric Dedoussis, George V.; Kaprio, Jaakko; Soranzo, Nicole; and Perinatal Epidemiology (Print), Vol. 26, No. 6, Spector, Tim D.; Collier, David A.; Zeggini, Eleftheria. 01.11.2012, p. 553-560. In: American journal of medical genetics. Part B, Neuropsychiatric genetics, Vol. 159B, No. 7, 01.10.2012, 7. Pubertal testosterone predicts mental rotation p. 803-811. performance of young adult males. / Vuoksimaa, Eero; Kaprio, Jaakko; Eriksson, Peter; Rose, Richard J. In: 14. Inter-tissue Networks Between the Basal Forebrain, Psychoneuroendocrinology, Vol. 37, No. 11, 01.11.2012, Hippocampus, and Prefrontal Cortex in a Model p. 1791-1800. for Depression Caused by Disturbed Sleep. / Lagus, Markus; Gass, Natalia; Saharinen, Juha; Savelyev, Sergey; 8. Effects of orkW and Lifestyle on Risk for Future Porkka-Heiskanen, Tarja; Paunio, Tiina. In: Journal of Disability Pension Due to Low Back Diagnoses A 30- Neurogenetics, Vol. 26, No. 3-4, 09.2012, p. 397-412.

FIMM • 85 15. Gene-Targeting of Phd2 Improves Tumor Response Amico Lago, Gabriela Veronica; Lampinen, Anita; Eklund, to Chemotherapy and Prevents Side-Toxicity. / de Lauri; Sormunen, Raija; Anisimov, Andrey; Zarkada, Oliveira, Rodrigo Leite; Deschoemaeker, Sofie; Henze, Georgia; Lohela, Marja Kaisa; Heloterä, Hanna; Tammela, Anne-Theres; Debackere, Koen; Finisguerra, Veronica; Tuomas; Benjamin, Laura; Ylä-Herttuala, Seppo; Leow, Takeda, Yukiji; Roncal, Carmen; Dettori, Daniela; Tack, Ching Ching; Koh, Gou Young; Alitalo, Kari. In: Journal Evelyne; Jönsson, Yannick; Veschini, Lorenzo; Peeters, of the National Cancer Institute, Vol. 104, No. 6, Annelies; Anisimov, Andrey; Hofmann, Matthias; Alitalo, 21.03.2012, p. 461-475. Kari; Baes, Myriam; D’hooge, Jan; Carmeliet, Peter; Mazzone, Massimiliano. In: Cancer Cell, Vol. 22, No. 2, 21. Genetic and environmental influences underlying 14.08.2012, p. 263-277. externalizing behaviors, cigarette smoking and illicit drug use across adolescence. / Korhonen, Tellervo; 16. Genetic Markers Enhance Coronary Risk Prediction Latvala, Antti; Dick, Danielle M. ; Pulkkinen, Lea; Rose, in Men: The MORGAM Prospective Cohorts. / Richard J.; Kaprio, Jaakko; Huizink, Anja C. In: Behavior Hughes, Maria F.; Saarela, Olli; Stritzke, Jan; Kee, Frank; Genetics, Vol. 42, No. 4, 18.02.2012, p. 614-625. Silander, Kaisa; Klopp, Norman; Kontto, Jukka; Karvanen, 22. Don’t give up on GWAS. / Sullivan, P.; 96 Psychiat Juha; Willenborg, Christina; Salomaa, Veikko; Virtamo, Genetics Investigators ; Kaprio, Jaakko. In: Molecular Jarmo; Amouyel, Phillippe; Arveiler, Dominique; Ferrieres, Psychiatry, Vol. 17, No. 1, 01.2012, p. 2-3. Jean; Wiklund, Per-Gunner; Baumert, Jens; Thorand, Barbara; Diemert, Patrick; Tregouet, David-Alexandre; 23. A phase II trial of gefitinib in patients with rising PSA Hengstenberg, Christian; Peters, Annette; Evans, Alun; following radical prostatectomy or radiotherapy. / Koenig, Wolfgang; Erdmann, Jeanette; Samani, Nilesh J.; Joensuu ,Greetta; Joensuu, Timo Kalevi; Nupponen, Nina Kuulasmaa, Kari; Schunkert, Heribert. In: PLoS One, Vol. Natalia; Ruutu, Mirja Liisa; Collan, Juhani; Pesonen, Sari; 7, No. 7, 25.07.2012, p. Article Number: e40922 . Hemminki, Akseli Eetu. In: Acta Oncologica, Vol. 51, No. 1, 2012, p. 130-133. 17. Deletion of the endothelial Bmx tyrosine kinase decreases tumor angiogenesis and growth. / 24. A study of candidate genes in depression and Holopainen, Tanja Talvikki; López Alpuche, V.; Zheng, Wei; disturbed sleep. / Utge, Siddheshwar J.Helsinki : Heljasvaara, R; Jones, D; He, Y.; Tvorogov, Denis; D Amico Terveyden ja hyvinvoinnin laitos, 2012. 130 p. (Research / Lago, Gabriela Veronica; Wiener, Zoltan; Andersson, National Institute for Health and Welfare; 81) Leif C.; Pihlajaniemi, T.; Min, W.; Alitalo, Kari. In: Cancer Research, Vol. 72, No. 14, 15.07.2012, p. 3512-3521. 25. Age and estrogen-based hormone therapy affect systemic and local IL-6 and IGF-1 pathways in 18. The association between waist circumference and women. / Ahtiainen, Maarit ; Pöllänen, Eija ; Ronkainen, risk of mortality considering body mass index in Paula H.A.; Alen, Markku; Puolakka, Jukka; Kaprio, 65-to 74-year-olds: a meta-analysis of 29 cohorts Jaakko; Sipilä, Sarianna; Kovanen, Vuokko. In: Age, Vol. involving more than 58 000 elderly persons. / de 34, No. 5, 2012, p. 1249-1260. Hollander, Ellen L.; Bemelmans, Wanda J. E.; Boshuizen, Hendriek C.; Friedrich, Nele; Wallaschofski, Henri; 26. Analysis of Detailed Phenotype Profiles Reveals Guallar-Castillon, Pilar; Walter, Stefan; Zillikens, M. CHRNA5-CHRNA3-CHRNB4 Gene Cluster Association Carola; Rosengren, Annika; Lissner, Lauren; Bassett, With Several Nicotine Dependence Traits. / Broms, Julie K.; Giles, Graham G.; Orsini, Nicola; Heim, Noor; Ulla; Wedenoja, Juho; Largeau, Marine R.; Korhonen, Visser, Marjolein; de Groot, Lisette C. P. G. M.; WC Elderly Tellervo; Pitkäniemi, Janne Mikael; Keskitalo, Kaisu; Collaborators ; Kaprio, Jaakko.In: International Journal of Happola, Anja; Heikkila, Katri H.; Heikkila, Kauko; Ripatti, Epidemiology, Vol. 41, No. 3, 06.2012, p. 805-817. Samuli; Sarin, Antti-Pekka; Salminen, Outi; Paunio, Tiina; Pergadia, Michele L.; Madden, Pamela A. F.; Kaprio, 19. Observ-OM and Observ-TAB: Universal Syntax Jaakko; Loukola, Anu. In: Nicotine & Tobacco Research, Solutions for the Integration, Search, and Exchange Vol. 14, No. 6, 2012, p. 720-733. of Phenotype And Genotype Information. / Adamusiak, Tomasz; Parkinson, Helen; Muilu, Juha; 27. Association between smoking behavior patterns and Roos, Erik; van der Velde, Kasper Joeri; Thorisson, chronic obstructive pulmonary disease : A long-term Gudmundur A.; Byrne, Myles; Pang, Chao; Gollapudi, follow-up study among Finnish adults. / Hukkinen, Sirisha; Ferretti, Vincent; Hillege, Hans; Brookes, Anthony Maria; Korhonen, Tellervo; Heikkilä, Kauko Veli; Kaprio, J.; Swertz, Morris A. In: Human Mutation, Vol. 33, No. 5, Jaakko. In: Annals of Medicine, Vol. 44, No. 6, 2012, p. 05.2012, p. 867-873. 598-606.

20. Effects of angiopoietin-2-blocking antibody on 28. Bayesian Variable Selection in Searching for Additive endothelial cell-cell junctions and lung metastasis. and Dominant Effects in Genome-Wide Data. / / Holopainen, Tanja Talvikki; Saharinen, Pipsa Ilona; D Peltola, Tomi; Marttinen, Pekka; Jula, Antti; Salomaa,

86 • FIMM Veikko; Perola, Markus; Vehtari, Aki. In: PLoS One, Vol. 7, Johanne; Daugaard, Mads; Egebjerg, Christina; No. 1, 2012, p. e29115. Bottzauw, Trine; Kohonen, Pekka; Nylandsted, Jesper; Hautaniemi, Sampsa; Moreira, Jose; Jaattela, Marja; 29. Caloric Restriction Ameliorates Angiotensin II- Kallunki, Tuula. In: Molecular Cell, Vol. 45, No. 6, 2012, p. Induced Mitochondrial Remodeling and Cardiac 764-776. Hypertrophy. / Finckenberg, Piet; Eriksson-Rosenberg, Ove; Baumann, Marc; Merasto, Saara; Lalowski, Maciej 36. Fear of falling and coexisting sensory difficulties M.; Levijoki, Jouko; Haasio, Kristiina; Kyto, Ville; Muller, as predictors of mobility decline in older women. Dominik N.; Luft, Friedrich C.; Oresic, Matej; Mervaala, / Viljanen, Anne; Kulmala, Jenni; Rantakokko, Merja; Eero. In: Hypertension Research, Vol. 59, 2012, p. 76-84. Koskenvuo, Markku; Kaprio, Jaakko; Rantanen, Taina. In: Journals of Gerontology. Series A: Biological Sciences and 30. Cancer of unknown primary (CUP): does cause Medical Sciences, Vol. 67, No. 11, 2012, p. 1230-1237. of death and family history implicate hidden phenotypically changed primaries?. / Hemminki, 37. Genetic Influences on Physical Activity in Young K.; Bevier, M.; Sundquist, J.; Hemminki, Akseli Eetu. In: Adults: A Twin Study. / Mustelin, Linda; Joutsi, Jessica; Annals of Oncology, Vol. 23, No. 10, 2012, p. 2720-2724. Latvala, Antti; Pietiläinen, Kirsi Hannele; Rissanen, Aila; Kaprio, Jaakko. In: Medicine and Science in Sports and 31. Chromosome 20 Shows Linkage With DSM-IV Exercise, Vol. 44, No. 7, 2012, p. 1293-1301. Nicotine Dependence in Finnish Adult Smokers. / Keskitalo, Kaisu; Hällfors, Jenni Katariina; Broms, Ulla; 38. Genetic and Environmental Influences on BMI From Pergadia, Michele L.; Saccone, Scott F.; Loukola, Anu; Late Childhood to Adolescence are Modified by Madden, Pamela A. F.; Kaprio, Jaakko. In: Nicotine & Parental Education. / Lajunen, Hanna-Reetta; Kaprio, Tobacco Research, Vol. 14, No. 2, 2012, p. 153-160. Jaakko; Rose, Richard J.; Pulkkinen, Lea; Silventoinen, Karri. In: Obesity, Vol. 20, No. 3, 2012, p. 583-589. 32. Common Genetic Variants Associated with Sudden Cardiac Death: The FinSCDgen Study. / Lahtinen, 39. Geographic Differences in Genetic Susceptibility Annukka M.; Noseworthy, Peter A.; Havulinna, Aki S.; Jula, to IgA Nephropathy: GWAS Replication Study and Antti; Karhunen, Pekka J.; Kettunen, Johannes; Perola, Geospatial Risk Analysis. / Kiryluk, Krzysztof; Li, Yifu; Markus; Kontula, Kimmo; Newton-Cheh, Christopher; Sanna-Cherchi, Simone; Rohanizadegan, Mersedeh; Salomaa, Veikko. In: PLoS One, Vol. 7, No. 7, 2012, p. Article Suzuki, Hitoshi; Eitner, Frank; Snyder, Holly J.; Choi, Number: e41675. Murim; Hou, Ping; Scolari, Francesco; Izzi, Claudia; Gigante, Maddalena; Gesualdo, Loreto; Savoldi, Silvana; 33. Diurnal evening type is associated with current Amoroso, Antonio; Cusi, Daniele; Zamboli, Pasquale; smoking, nicotine dependence and nicotine intake in Julian, Bruce A.; Novak, Jan; Wyatt, Robert J.; Mucha, the population based national FINRISK 2007 study. / Krzysztof; Perola, Markus; Kristiansson, Kati; Viktorin, Broms, Ulla Heidi; Pennanen, Marjaana; Patja, Kristiina; Alexander; Magnusson, Patrik K.; Thorleifsson, Gudmar; Ollila, Hanna; Korhonen, Tellervo; Kankaanpää, Aino; Thorsteinsdottir, Unnur; Stefansson, Kari; Boland, Anne; Haukkala, Ari; Tuulio-Henriksson, Annamari; Koskenvuo, Metzger, Marie; Thibaudin, Lise; Wanner, Christoph; Markku; Kronholm, Erkki; Laatikainen, Tiina; Peltonen, Jager, Kitty J.; Goto, Shin; Maixnerova, Dita; Karnib, Markku; Partonen, Timo; Kaprio, Jaakko. In: Addiction Hussein H.; Nagy, Judit; Panzer, Ulf; Xie, Jingyuan; Chen, Research & Therapy, Vol. 2012, 2012, p. S2. Nan; Tesar, Vladimir; Narita, Ichiei; Berthoux, Francois; Floege, Juergen; Stengel, Benedicte; Zhang, Hong; Lifton, 34. Effects of capsid-modified oncolytic adenoviruses Richard P.; Gharavi, Ali G. In: PLoS Genetics, Vol. 8, No. 6, and their combinations with gemcitabine or silica 2012, p. Article Number: e1002765. gel on pancreatic cancer. / Kangasniemi, Lotta; Parviainen, Suvi; Pisto, Tommi; Koskinen, Mika ; Jokinen, 40. Immune Response Is an Important Aspect of the Mika; Kiviluoto, Tuula Anneli; Cerullo, Vincenzo; Jalonen, Antitumor Effect Produced by a CD40L-Encoding Harry ; Koski, Anniina Kaisa Elina; Kangasniemi, Anna; Oncolytic Adenovirus. / Diaconu, Iulia; Cerullo, Kanerva, Anna; Pesonen, Sari; Hemminki, Akseli Eetu. In: Vincenzo; Hirvinen, Mari L. M.; Escutenaire, Sophie; International Journal of Cancer, Vol. 131, No. 1, 2012, p. Ugolini, Matteo; Pesonen, Saila K.; Bramante, Simona; 253-263. Parviainen, Suvi; Kanerva, Anna-Maija; Loskog, Angelica S. I.; Eliopoulos, Aristides G.; Pesonen, Sari; Hemminki, 35. ErbB2-Driven Breast Cancer Cell Invasion Depends Akseli. In: Cancer Research, Vol. 72, No. 9, 2012, p. 2327- on a Complex Signaling Network Activating Myeloid 2338. Zinc Finger-1-Dependent Cathepsin B Expression. / Rafn, Bo; Nielsen, Christian Friberg; Andersen, Sofie 41. Indoleamine 2,3-dioxygenase activation and Hagel; Szyniarowski, Piotr; Corcelle-Termeau, Elisabeth; depressive symptoms : Results from the young Valo, Erkka; Fehrenbacher, Nicole; Olsen, Charlotta finns study. / Elovainio, M.; Hurme, M.; Jokela, M.;

FIMM • 87 Pulkki-Råback, L.; Kivimäki, M.; Hintsanen, M.; Hintsa, Danielson; Patrik Sandström; Johanna Vakkuri. Helsinki: T.; Lehtimäki, T.; Viikari, J.; Raitakari, O.T.; Keltikangas- Terveyden ja hyvinvoinnin laitos, 2012. p. 106-120 Järvinen, L. In: Psychosomatic Medicine, Vol. 74, No. 7, (Teema / Terveyden ja hyvinvoinnin laitos ; 16). 2012, p. 675-681. 49. No Association of COMT (Val158Met) Genotype 42. Inhibition of cyclooxygenase-2 causes regression of with Brain Structure Differences between Men gastric adenomas in trefoil factor 1 deficient mice. and Women. / Barnes, Anna; Isohanni, Matti; Barnett, / Thiel, Alexandra; Narko, Kirsi; Heinonen, Mira Marie; Jennifer H.; Pietiläinen, Olli; Veijola, Juha; Miettunen, Hemmes, Annabrita; Tomasetto, Catherine; Rio, Marie- Jouko; Paunio, Tiina; Tanskanen, Paivikki; Ridler, Christine; Haglund, Caj; Mäkelä, Tomi; Ristimäki, Ari. In: Khanum; Suckling, John; Bullmore, Edward T.; Murray, International Journal of Cancer, Vol. 131, No. 5, 2012, p. Graham K.; Jones, Peter B. In: PLoS One, Vol. 7, No. 3, 1032-1041. 2012, p. Article Number: e33964.

43. Integrin targeted oncolytic adenoviruses Ad5-D24- 50. Oncolytic Immunotherapy of Advanced Solid RGD and Ad5-RGD-D24-GMCSF for treatment of Tumors with a CD40L-Expressing Replicating patients with advanced chemotherapy refractory Adenovirus: Assessment of Safety and Immunologic solid tumors. / Pesonen, Sari; Diaconu, Iulia; Cerullo, Responses in Patients. / Pesonen, Sari; Diaconu, Iulia; Vincenzo; Escutenaire, Sophie; Raki, Mari; Kangasniemi, Kangasniemi, Lotta; Ranki, Tuuli; Kanerva, Anna-Maija; Lotta; Nokisalmi, Petri; Dotti, Gianpietro; Guse, Kilian; Pesonen, Saila K.; Gerdemann, Ulrike; Leen, Ann M.; Laasonen, Leena; Partanen, Kaarina; Karli, Eerika; Kairemo, Kalevi; Oksanen, Minna; Haavisto, Elina; Haavisto, Elina; Oksanen, Minna Kristina; Karioja-Kallio, Sirkka-Liisa, Holm ; Karioja-Kallio, Aila; Kauppinen, Satu; Aila; Hannuksela, Päivi ; Sirkka-Liisa, Holm ; Kauppinen, Partanen, Kaarina P. L.; Laasonen, Leena; Joensuu, Tima; Satu; Joensuu, Timo Kalevi; Kanerva, Anna; Hemminki, Alanko, Tuomo; Cerullo, Vincenzo; Hemminki, Akseli. In: Akseli Eetu. In: International Journal of Cancer, Vol. 130, Cancer Research, Vol. 72, No. 7, 2012, p. 1621-1631. No. 8, 2012, p. 1937-1947. 51. Pathology of Breast and Ovarian Cancers among 44. Macrophage metalloelastase (MME) as adjuvant for BRCA1 and BRCA2 Mutation Carriers: Results from intra-tumoral injection of oncolytic adenovirus and the Consortium of Investigators of Modifiers of its influence on metastases development. / Lavilla BRCA1/2 (CIMBA). / Mavaddat, Nasim; Barrowdale, Alonso, Sergio; Bauer, M M T ; Abo-Ramadan, Usama; Daniel; Andrulis, Irene L.; Domchek, Susan M.; Eccles, Ristimäki, Ari; Halavaara, Juha Tapio; Desmond, A; Diana; Nevanlinna, Heli; Ramus, Susan J.; Spurdle, Wang, D; Escutenaire, Sophie; Ahtiainen, Laura Kaarina; Amanda; Robson, Mark; Sherman, Mark; Mulligan, Saksela, Kalle; Tatlisumak, Turgut; Hemminki, Akseli Anna Marie; Couch, Fergus J.; Engel, Christoph; Eetu; Pesonen, Sari. In: Cancer Gene Therapy, Vol. 19, No. McGuffog, Lesley; Healey, Sue; Sinilnikova, Olga M.; 2, 2012, p. 126-134. Southey, Melissa C.; Terry, Mary Beth; Goldgar, David; O’Malley, Frances; John, Esther M.; Janavicius, Ramunas; 45. Motives for and barriers to physical activity in twin Tihomirova, Laima; Hansen, Thomas V. O.; Nielsen, pairs discordant for leisure time physical activity for Finn C.; Osorio, Ana; Stavropoulou, Alexandra; Benitez, 30 years. / Aaltonen, S; Leskinen, T; Morris, T; Alen, M; Javier; Manoukian, Siranoush; Peissel, Bernard; Barile, Kaprio, Jaakko; Liukkonen, J; Kujala, U. In: International Monica; Volorio, Sara; Pasini, Barbara; Dolcetti, Riccardo; journal of sports medicine, Vol. 33, No. 2, 2012, p. 157- Putignano, Anna Laura; Ottini, Laura; Radice, Paolo; 163. Hamann, Ute; Rashid, Muhammad U.; Hogervorst, Frans B.; Kriege, Mieke; van der Luijt, Rob B.; Peock, Susan; 46. Netrin-4 Promotes Glioblastoma Cell Proliferation Frost, Debra; Evans, D. Gareth; Brewer, Carole; Walker, through Integrin beta(4) Signaling. / Hu, Yizhou; Lisa; Rogers, Mark T.; Side, Lucy E.; Houghton, Catherine; Ylivinkka, Irene; Chen, Ping; Li, Li; Hautaniemi, Sampsa; Weaver, JoEllen; Godwin, Andrew K.; Schmutzler, Rita K.; Nyman, Tuula A.; Keski-Oja, Jorma; Hyytiainen, Marko. Wappenschmidt, Barbara; Meindl, Alfons; Kast, Karin; In: NeoPlasia, Vol. 14, No. 3, 2012, p. 219-227. Arnold, Norbert; Niederacher, Dieter; Sutter, Christian; 47. Nikotiiniriippuvuuden genetiikka. / Korhonen, Deissler, Helmut; Gadzicki, Doroteha; Preisler-Adams, Tellervo; Kaprio, Jaakko. In: Duodecim, Vol. 128, No. 10, Sabine; Varon-Mateeva, Raymonda; Schoenbuchner, 2012, p. 1065-1071. Ines; Gevensleben, Heidrun; Stoppa-Lyonnet, Dominique; Belotti, Muriel; Barjhoux, Laure; Isaacs, Claudine; 48. Nikotiiniriippuvuus on moniulotteinen sairaus. Peshkin, Beth N.; Caldes, Trinidad; de la Hoya, Miguel; / Broms, Ulla Heidi; Korhonen, Tellervo; Salminen, Canadas, Carmen; Heikkinen, Tuomas; Heikkila, Paivi; Outi; Pennanen, Marjaana; Kaprio, Jaakko. In: Towards Aittomaki, Kristiina; Blanco, Ignacio; Lazaro, Conxi; tobacco-free Finland: Changes in tobacco use and Brunet, Joan; Agnarsson, Bjarni A.; Arason, Adalgeir; tobacco policy.. ed. / Antero Heloma; Hanna Ollilla; Petri Barkardottir, Rosa B.; Dumont, Martine; Simard, Jacques;

88 • FIMM Montagna, Marco; Agata, Simona; D’Andrea, Emma; Yan, Abdel-Rahman, W. M.; Ovaska, K.; Siggberg, L.; Aapola, Max; Fox, Stephen; Rebbeck, Timothy R.; Rubinstein, U.; Assamaki, R.; Hayry, V.; Niiranen, K.; Helle, M.; Wendy; Tung, Nadine; Garber, Judy E.; Wang, Xianshu; Knuutila, S.; Hautaniemi, S.; Peltomaki, P.; Krohn, K. In: Fredericksen, Zachary; Pankratz, Vernon S.; Lindor, British Journal of Cancer, Vol. 106, 2012, p. 517-524. Noralane M.; Szabo, Csilla; Offit, Kenneth; Sakr, Rita; Gaudet, Mia M.; Singer, Christian F.; Tea, Muy-Kheng; 57. Power and limits of modern cancer diagnostics: Rappaport, Christine; Mai, Phuong L.; Greene, Mark H.; cancer of unknown primary. / Hemminki, K.; Liu, Sokolenko, Anna; Imyanitov, Evgeny; Toland, Amanda H.; Hemminki, Akseli Eetu; Sundquist, J. In: Annals of Ewart; Senter, Leigha; Sweet, Kevin; Thomassen, Mads; Oncology, Vol. 23, No. 3, 2012, p. 760-764. Gerdes, Anne-Marie; Kruse, Torben; Caligo, Maria; 58. Prevention of Premature Fusion of Calvarial Suture Aretini, Paolo; Rantala, Johanna; von Wachenfeld, Anna; in GLI-Kruppel Family Member 3 (Gli3)-deficient Henriksson, Karin; Steele, Linda; Neuhausen, Susan Mice by Removing One Allele of Runt-related L.; Nussbaum, Robert; Beattie, Mary; Odunsi, Kunle; Transcription Factor 2 (Runx2). / Tanimoto, Yukiho; Sucheston, Lara; Gayther, Simon A.; Nathanson, Kate; Veistinen, Lotta; Alakurtti, Kirsi; Takatalo, Maarit; Rice, Gross, Jenny; Walsh, Christine; Karlan, Beth; Chenevix- David P. C. In: Journal of Biological Chemistry, Vol. 287, Trench, Georgia; Easton, Douglas F.; Antoniou, Antonis 2012, p. 21429-21438. C.; EMBRACE, Consortium Investigators Modifiers, SWE- BRCA Collaborators, HEBON, kConFab Investigators, 59. Radiation-Induced Upregulation of Gene Expression GEMO Study Collaborators. In: Cancer Epidemiology, From Adenoviral Vectors Mediated by DNA Damage Biomarkers & Prevention, Vol. 21, No. 1, 2012, p. 134- Repair and Regulation. / Nokisalmi, Petri; Rajecki, 147. Maria; Pesonen, Sari; Escutenaire, Sophie; Soliymani, Rabah; Tenhunen, Mikko; Ahtiainen, Laura; Hemminki, 52. Personal goals and personality traits among young Akseli. In: International Journal of Radiation: Oncology - adults: Genetic and environmental effects. / Salmela- Biology - Physics, Vol. 83, No. 1, 2012, p. 376-384. Aro, Katariina; Read, Sanna; Nurmi, Jari-Erik; Vuoksimaa, Eero; Siltala, Mari; Dick, Danielle M.; Pulkkinen, Lea; 60. Selective spatiotemporal patterns of glial activation Kaprio, Jaakko; Rose, Richard J. In: Journal of Research in and neuron loss in the sensory thalamocortical Personality, Vol. 46, No. 3, 2012, p. 248-257. pathways of neuronal ceroid lipofuscinosis 8 mice. / Kuronen, Mervi; Lehesjoki, Anna-Elina; Jalanko, Anu; 53. Personality traits and life dissatisfaction as risk Cooper, Jonathan D.; Kopra, Outi. In: Neurobiology of factors for disability pension due to low back Disease, Vol. 47, No. 3, 2012, p. 444-457. diagnoses : A 30-year longitudinal cohort study of Finnish twins. / Ropponen, Annina; Svedberg, 61. Self-reported life satisfaction and alcohol use : A Pia; Huunan-Seppälä, Antti; Koskenvuo, Karoliina; 15-year follow-up of healthy adult twins. / Koivumaa- Koskenvuo, Markku; Alexanderson, Kristina; Honkanen, H.; Kaprio, J.; Korhonen, T.; Honkanen, R. J.; Silventoinen, Karri; Kaprio, Jaakko. In: Journal of Heikkila, K.; Koskenvuo, M. In: Alcohol and Alcoholism, Psychosomatic Research, Vol. 73, No. 4, 2012, p. 289- Vol. 47, No. 2, 2012, p. 160-168. 294. 62. Silencing of OSBP-related protein 8 (ORP8) modifies 54. Phospholipids and insulin resistance in psychosis the macrophage transcriptome, nucleoporin p62 : a lipidomics study of twin pairs discordant for distribution, and migration capacity. / Beaslas, schizophrenia. / Oresic, Matej; Seppänen-Laakso, Olivier; Vihervaara, Terhi; Li, Jiwei; Laurila, Pirkka-Pekka; Tuulikki; Sun, Daqiang; Tang, Jing; Therman, Sebastian; Yan, Daoguang; Olkkonen, Vesa M. In: Experimental Cell Viehman, Rachael; Mustonen, Ulla; van Erp, Theo G.M.; Research, Vol. 318, No. 15, 2012, p. 1933-1945. Hyötyläinen, Tuulia; Thompson, Paul; Toga, Arthur W.; Huttunen, Matti O.; Suvisaari, Jaana; Kaprio, Jaakko; 63. Sleep Modifies Metabolism Commentary onWatson Lönnqvist, Jouko; Cannon, Tyrone D. In: Genome medicine, et al. Sleep duration and body mass index in twins: Vol. 4, No. 1, 2012. a gene-environment interaction. SLEEP 2012;35:597- 603. / Paunio, Tiina. In: Sleep., Vol. 35, No. 5, 2012, p. 55. Pleasantness of the odor of androstenone as a 589-590. function of sexual intercourse experience in women and men. / Knaapila, Antti; Tuorila, Hely; Vuoksimaa, 64. Stress and survival after cancer : A prospective Eero; Keskitalo-Vuokko, Kaisu; Rose, Richard J; Kaprio, study of a Finnish population-based cohort. / Saito- Jaakko; Silventoinen, Karri. In: Archives of Sexual Nakaya, Kumi; Bidstrup, Pernille E.; Nakaya, Naoki; Behavior, Vol. 41, No. 6, 2012, p. 1403-1408. Frederiksen, Kirsten; Dalton, Susanne O.; Uchitomi, Yosuke; Verkasalo, Pia; Koskenvuo, Markku; Pukkala, 56. Potential role of a navigator gene NAV3 in colorectal Eero; Kaprio, Jaakko; Johansen, Christoffer. In: Cancer cancer. / Carlsson, E.; Ranki, A.; Sipila, L.; Karenko, L.; Epidemiology, Vol. 36, No. 2, 2012, p. 230-235.

FIMM • 89 65. Support for involvement of glutamate 69. Tobaksepidemin: epdemiologi, etiologi och decarboxylase 1 and neuropeptide y in anxiety behandling. / Korhonen, Tellervo; Kinnunen, Taru; susceptibility. / Donner, Jonas; Sipila, Tessa; Ripatti, Kaprio, Jaakko. In: Finska Läkaresällskapets Handlingar, Samuli; Kananen, Laura; Chen, Xiangning; Kendler, Vol. 172, No. 2, 2012, p. 34-39. Kenneth S.; Lönnqvist, Jouko; Pirkola, Sami; Hettema, John M.; Hovatta, Iiris. In: American journal of medical 70. Tupakoinnin lopettaminen Suomessa 1997- genetics. Part B, Neuropsychiatric genetics, Vol. 159B, 2007: Vain kolmasosa saa lopettamiskehotuksen No. 3, 2012, p. 316-327. terveydenhuollosta. / Ollila, Hanna; Patja, Kristiina; Broms, Ulla Heidi; Korhonen, Tellervo; Haukkala, Ari; 66. Survival in cancer of unknown primary site: Kaprio, Jaakko. In: Suomen lääkärilehti, Vol. 67, No. 48, population-based analysis by site and histology. 2012, p. 3569-3576. / Hemminki, K.; Bevier, M.; Hemminki, Akseli Eetu; Sundquist, J. In: Annals of Oncology, Vol. 23, No. 7, 2012, 71. Verapamil results in increased blood levels of p. 1854-1863. oncolytic adenovirus in treatment of patients with advanced cancer. / Koski, Anniina Kaisa Elina; Raki, 67. Targeted cancer immunotherapy with oncolytic Mari; Nokisalmi, Petri; Liikanen, Ilkka; Kangasniemi, adenovirus coding for a fully human monoclonal Lotta; Joensuu, Timo Kalevi; Kanerva, Anna; Pesonen, antibody specific for CTLA-4. / Afonso De Carvalho Sari; Alemany, Ramon; Hemminki, Akseli Eetu. In: Dias, Joao Daniel; Hemminki, Otto; Diaconu, Iulia; Molecular therapy, Vol. 20, No. 1, 2012, p. 221-229. Hirvinen, M; Bonetti, Alessandro; Guse, Kilian; Escutenaire, Sophie; Kanerva, Anna-Maija; Pesonen, Sari; 72. Weight growth of triplet infants from birth to Löskog, A; Cerullo, Vincenzo; Hemminki, Akseli Eetu. In: twelve years of age. / Yokoyama, Yoshie; Pitkäniemi, Gene Therapy (Basingstoke), Vol. 19, No. 10, 2012, p. Janne Mikael; Kaprio, Jaakko; Silventoinen, Karri. In: Twin 988-998. Research and Human Genetics, Vol. 15, No. 5, 2012, p. 672-679. 68. Thymidine kinase 2 mutations in autosomal recessive progressive external ophthalmoplegia with multiple 73. Why do some like it hot? Genetic and environmental mitochondrial DNA deletions. / Tyynismaa, Henna; Sun, contributions to the pleasantness of oral pungency. Ren; Ahola-Erkkila, Sofia; Almusa, Henrikki; Poyhonen, / Törnwall, Outi; Silventoinen, Karri; Kaprio, Jaakko; Rosanna; Korpela, Mari Päivikki; Honkaniemi, Jari; Tuorila, Hely. In: Physiology & Behavior, Vol. 107, No. 3, Isohanni, Pirjo; Paetau, Anders; Wang, Liya; Suomalainen, 2012, p. 381-389. Anu. In: Human Molecular Genetics, Vol. 21, No. 1, 2012, p. 66-75.

FIMM Annual Report 2012 Annual Report

ANNUAL REPORT 2012

www.fimm.fi • P.O. Box 20, FI-00014 University of Helsinki, Finland • Biomedicum Helsinki 2U, Tukholmankatu 8, 00290 Helsinki, Finland