European Journal of Human Genetics (2011) 19, S6–S44 & 2011 Macmillan Publishers Limited All rights reserved 1018-4813/11 www.nature.com/ejhg POLICY Genetic testing and common disorders in a public health framework: how to assess relevance and possibilities Background Document to the ESHG recommendations on genetic testing and common disorders Frauke Becker1,26, Carla G van El2,26, Dolores Ibarreta3, Eleni Zika3, Stuart Hogarth4, Pascal Borry2,5,6, Anne Cambon-Thomsen7, Jean Jacques Cassiman8, Gerry Evers-Kiebooms9, Shirley Hodgson10, ACe´cile JW Janssens11, Helena Kaariainen12, Michael Krawczak13, Ulf Kristoffersson14, Jan Lubinski15, Christine Patch16, Victor B Penchaszadeh17, Andrew Read18, Wolf Rogowski19,20, Jorge Sequeiros21, Lisbeth Tranebjaerg22, Irene M van Langen23, Helen Wallace24, Ron Zimmern25,Jo¨rg Schmidtke1 and Martina C Cornel*,2 European Journal of Human Genetics (2011) 19, S6–S44; doi:10.1038/ejhg.2010.249 Keywords: common disorders; genetic testing; predictive value; monogenic subtypes; public health INTRODUCTION environment interactions. We will use the term ‘complex disease’ Background and purpose to indicate diseases with variable etiology, including multifactorial During the years prior to the turn of the century, scientific and etiology as well as monogenic subsets. When discussing ‘susceptibility medical attention for genetic disorders was mainly focused on under- genes’ in this document, we refer to genetic variants with low standing rare single-gene disorders, such as Huntington’s disease, predictive value. We need to admit, however, that no generally Duchenne muscular dystrophy, and cystic fibrosis (CF), as well as accepted threshold for categorizing predictive value levels exists. chromosomal abnormalities. The medical specialty of clinical genetics Researchers nowadays study the myriad of genetic polymorphisms was established in the 1980s and 1990s in many European countries to that have been identified during and since the Human Genome diagnose these kinds of rare disorders and to counsel patients and Project. The spectacular growth of genome-wide association studies1 families. has shed new light on which of these variants represent risk factors for In recent years, the attention of the genomics and genetics research common diseases. Understanding the pathogenesis and etiology, and community has shifted toward understanding the basis of common finding new ways to prevent and treat those diseases are major complex disorders. Common diseases are diseases frequently encoun- challenges. The traits or diseases under study include coronary artery tered in health care. Some cases of common disorders are character- disease, myocardial infarction, stroke, peripheral artery disease, obe- ized by a strong influence of germline mutations in a single gene; these sity, type 1 diabetes, type 2 diabetes, breast cancer, cervical cancer, will be referred to as ‘monogenic subtypes’. In many cases common colorectal cancer, prostate cancer, celiac disease, bipolar disorder, disorders have a multifactorial etiology: they are caused by several Crohn’s disease, and many more. Should incorporation of these genes and environmental factors, involving gene–gene and/or gene– research results into current clinical and public health practice become 1Hannover Medical School, Department of Human Genetics, Hannover, Germany; 2Department of Clinical Genetics and EMGO Institute for Health and Care Research, VU University Medical Center, Amsterdam, The Netherlands; 3IPTS Institute for Prospective Technological Studies, Joint Research Centre, European Commission, Seville, Spain; 4Department of Social Sciences, Loughborough University, Loughborough, UK; 5Centre for Biomedical Ethics and Law, Katholieke Universiteit Leuven, Leuven, Belgium; 6Department of Medical Humanities and EMGO Institute for Health and Care Research, VU University Medical Center, Amsterdam, The Netherlands; 7Inserm, U 558, Department of Epidemiology, Health Economics and Public Health, University Paul Sabatier, Toulouse, France; 8Center for Human Genetics, University of Leuven, Leuven, Belgium; 9Psychosocial Genetics Unit University Hospitals, Katholieke Universiteit Leuven, Leuven, Belgium; 10Department of Clinical Genetics, St George’s University of London, London, UK; 11Department of Epidemiology, Erasmus MC University Medical Center, Rotterdam, The Netherlands; 12National Institute for Health and Welfare, Helsinki, Finland; 13Institute of Medical Informatics and Statistics, Christian-Albrechts-Universita¨t, Kiel, Germany; 14Department of Clinical Genetics, University Hospital, Lund, Sweden; 15Department of Genetics and Pathology, International Hereditary Cancer Center, Pomeranian Medical University, Szczecin, Poland; 16Guys and St Thomas’ NHS Foundation Trust, London, UK; 17Mailman School of Public Health, Columbia University, New York, NY, USA; 18Division of Human Development, School of Clinical Sciences, University of Nottingham, Nottingham, UK; 19Helmholtz Center Munich, German Research Center for Environmental Health (GmbH), Neuherberg, Germany; 20Institute and Outpatient Clinic for Occupational, Social and Environmental Medicine, Clinical Center, Ludwig Maximilians University, Munich, Germany; 21IBMC – Institute for Molecular and Cell Biology, and ICBAS, University of Porto, Porto, Portugal; 22Department of Audiology, H:S Bispebjerg Hospital and Wilhelm Johannsen Centre of Functional Genomics, University of Copenhagen, Copenhagen, Denmark; 23Department of Genetics, University Medical Center Groningen and University of Groningen, Groningen, The Netherlands; 24GeneWatch UK, The Mill House, Tideswell, Derbyshire, UK; 25PHG Foundation, Worts Causeway, Cambridge, UK *Correspondence: Professor MC Cornel, Department of Clinical Genetics and EMGO Institute for Health and Care Research, VU University Medical Center, BS7, D423, PO Box 7057, 1007 MB Amsterdam, The Netherlands. Tel: +31 20 4448910; Fax: +31 20 4448181; E-mail: [email protected] 26These authors contributed equally to this work. ESHG background document genetic testing and common disorders FBeckeret al S7 possible, then researchers and practitioners have to be prepared for the services and at improving the overall quality of genetic services offered way in which this changes their daily routine.2–8 within the EU. This includes both the establishment of procedures and The clinical management of information about frequently occurring guidelines for the validation of methods and technologies and DNA variants that lead to moderate increases in risks for common the provision of quality-assured information sources to medical diseases requires a different approach from that of the significantly professionals, as well as proper utilization of genetic services. The increased genetic risks for numerous rare health problems. Translation IPTS is one of the seven scientific institutes of the European Commis- of research findings to useful health-care applications appears to be sion’s Joint Research Centre (JRC). It informs EU policy making on lagging behind. Implementation of useful research findings may take issues with a socioeconomic and a scientific or technological dimension. years or decades. Meanwhile, some applications of very limited clinical After the Seville workshop, to enable further discussion on some utility have become available directly to the consumers. Difficulties genetic epidemiological issues, a workshop was organized in Septem- with the translation of research findings need to be understood and ber 2008 in Amsterdam. The background document was revised into addressed if genetics and genomics research is to fulfil its promises its present form on the basis of comments by participants of both towards improving diagnosis, treatment, and prevention. Currently meetings and other experts, some of whom are active in the EU- (in 2010) the genetics research community is skeptical about the funded Public Health Genomic European Network (PHGEN, http:// possibilities of genetic susceptibility testing and screening contributing www.phgen.eu) project and the international GRAPH-Int (http:// significantly to the improvement of the quality of health care. The www.graphint.org) consortium that was established under the Cana- implementation in health care of genetic tests that are considered dian Public Health Agency. These organizations have been established useful should overcome several thresholds. to promote, at both the European and the global level, responsible and Health promotion and disease prevention for the population at effective translation of genome-based knowledge and technologies large has been the domain of public health professionals; yet, public into public policy and public health services. health approaches have thus far not taken into account genetic risk Suggestions were incorporated in the background document, and factors and often not even family history.9 So far, advice on lifestyle, during the process the PPPC discussed the recommendations. A draft physical activity, and nutrition has been developed in a one-size-fits- of the background document and recommendations were distributed all approach.6 The era of genomics presents the promise of persona- and posted on the web during the summer of 2009 to elicit further lized prevention and drug treatment, which has been met with comments. After this procedure the draft was revised. The PPPC and enthusiasm by many people, but called into question by others.10 the Board of the ESHG approved the final version. This final text is In the light of these