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Genetic architecture of sporadic frontotemporal dementia and overlap with Alzheimer's and Parkinson's diseases

Reference: Ferrari Rafaelle, Wang Yungpeng, Vandrovcova Jana, Van Broeckhoven Christine [medewerker], et. al.- Genetic architecture of sporadic frontotemporal dementia and overlap with Alzheimer's and Parkinson's diseases Journal of neurology, neurosurgery and psychiatry - ISSN 0022-3050 - 88:2(2017), p. 152-164 Full text (Publisher's DOI): http://dx.doi.org/doi:10.1136/JNNP-2016-314411

Institutional repository IRUA Methods We performed a 2-stage genome wide association study (GWAS) on clinical FTD analyzing a total of 3,526 FTD cases and 9,402 controls with European ancestry. We conducted separate association analyses for each FTD subtype (behavioural variant FTD [bvFTD], semantic dementia [SD], progressive non-fluent aphasia [PNFA], and FTD overlapping with motor neuron disease [FTD-MND]) and then meta-analyzed the entire dataset in discovery phase (2,154 cases vs. 4,308 controls). We carried forward replication of the novel suggestive loci in an independent sample series (1,372 cases vs. 5,094 controls) and then performed joint phase and brain e/mQTL (expression/methylation quantitative trait loci) analyses for the associated and suggestive SNPs.

Findings We identified novel associations exceeding the genome wide significance threshold (p-value<5x10-8) that encompassed the HLA locus at 6p21·3 in the entire cohort. We also identified a potential novel locus at 11q14, encompassing RAB38/CTSC for the bvFTD subtype. Analysis of expression and methylation quantitative trait loci (e/mQTL) data suggested that these loci might affect expression and methylation in-cis.

Interpretation This study points to immune system processes (link to 6p21·3) and possibly to lysosomal and autophagy pathways (link to 11q14) as potentially involved in FTD. The new loci will need to be replicated in future studies to better define their association with disease and possibly shed light on the pathomechanisms contributing to FTD.

Funding Intramural funding from the National Institute of Neurological Disorders and Stroke (NINDS) and National Institute on Aging (NIA), the Wellcome/MRC Centre on Parkinson's disease, Alzheimer's Research UK (ARUK), and Texas Tech University Health Sciences Center (TTUHSC) office of the Dean.

Manuscript

Frontotemporal dementia and its subtypes: a genome wide association study

Raffaele Ferrari1,2’MSc, Dena G Hernandez2,3’MSc, Michael A Nalls3’PhD, Jonathan D Rohrer2,72’PhD, Adaikalavan Ramasamy2,89PhD, John BJ Kwok6,7PhD, Carol Dobson-Stone6,7PhD, William S Brooks6,7MBBS, Peter R Schofield6,7DSc, Glenda M Halliday6,7PhD, John R Hodges6,7MD, Olivier Piguet6,7PhD, Lauren Bartley6MSc, Elizabeth Thompson8,9MD, Eric Haan8,9MBBS, Isabel Hernández10MD, Agustín Ruiz10 MD, Mercè Boada10,11 MD, Barbara Borroni12MD, Alessandro Padovani12MD, Carlos Cruchaga13,14PhD, Nigel J Cairns14,15PhD, Luisa Benussi16PhD, Giuliano Binetti16MD, Roberta Ghidoni17PhD, Gianluigi Forloni18PhD, Daniela Galimberti19,20PhD, Chiara Fenoglio19,20PhD, Maria Serpente19,20PhD, Elio Scarpini19,20MD, Jordi Clarimón21,22PhD, Alberto Lleó21,22MD, Rafael Blesa21,22MD, Maria Landqvist Waldö23MD, Karin Nilsson23PhD, Christer Nilsson24PhD, Ian RA Mackenzie25MD, Ging-Yuek R Hsiung26MD, David MA Mann27PhD, Jordan Grafman28,29PhD, Christopher M Morris30,31,32PhD, Johannes Attems31MD, Timothy D Griffiths32 FMedSci, Ian G McKeith33MD, Alan J Thomas31PhD, Pietro Pietrini34MD, Edward D Huey35MD, Eric M Wassermann36MD, Atik Baborie37MD, Evelyn Jaros31,38PhD, Michael C Tierney36MSc, Pau Pastor39,40,22MD, Cristina Razquin39PhD, Sara Ortega-Cubero39,22MD, Elena Alonso39 BSc, Robert Perneczky41,42,43MD, Janine Diehl-Schmid43MD, Panagiotis Alexopoulos43MD, Alexander Kurz43MD, Innocenzo Rainero44MD, Elisa Rubino44MD, Lorenzo Pinessi44MD, Ekaterina Rogaeva45PhD, Peter St George-Hyslop45,46MD, Giacomina Rossi47PhD, Fabrizio Tagliavini47MD, Giorgio Giaccone47MD, James B Rowe48,49,50PhD, Johannes CM Schlachetzki51,52MD, James Uphill53 BSc, John Collinge53MD, Simon Mead53PhD, Adrian Danek54,55MD, Vivianna M Van Deerlin56PhD, Murray Grossman56MD, John Q Trojanowski56PhD, Julie van der Zee57,58PhD, William Deschamps57,58MSc, Tim Van Langenhove57,58MD, Marc Cruts57,58PhD, Christine Van Broeckhoven57,58PhD, The Belgian Neurology Consortium and the European Early-Onset Dementia consortium, Stefano F Cappa59MD, Isabelle Le Ber60,61MD, Didier Hannequin62MD, Véronique Golfier63MD, Martine Vercelletto64MD, Alexis Brice60,61MD, The French research network on FTLD/FTLD-ALS, Benedetta Nacmias65PhD, Sandro Sorbi65PhD, Silvia Bagnoli65PhD, Irene Piaceri65PhD, Jørgen E Nielsen66,67MD, Lena E Hjermind66,67MD, Matthias Riemenschneider68,69MD, Manuel Mayhaus69PhD, Bernd Ibach70PhD, Gilles Gasparoni69PhD, Sabrina Pichler69MSc, Wei Gu69,71PhD, Martin N Rossor72MD, Nick C Fox72MD, Jason D Warren72PhD, Maria Grazia Spillantini73PhD, Huw R Morris74PhD, Patrizia Rizzu75PhD, Peter Heutink75PhD, Julie S Snowden5PhD, Sara Rollinson5PhD, Anna Richardson76MB, Alexander Gerhard77MD, Amalia C Bruni78MD, Raffaele Maletta78MD, Francesca Frangipane78MD, Chiara Cupidi78MD, Livia Bernardi78PhD, Maria Anfossi78PhD, Maura Gallo78PhD, Maria Elena Conidi78PhD, Nicoletta Smirne78BSc, Rosa Rademakers79PhD, Matt Baker79BSc, Dennis W Dickson79MD, Neill R Graff-Radford80MD, Ronald C Petersen81MD, David Knopman81MD, Keith A Josephs81MD, Bradley F Boeve81MD, Joseph E Parisi82MD, William W Seeley83MD, Bruce L Miller84MD, Anna M Karydas84BA, Howard Rosen84MD, John C van Swieten85,86MD, Elise GP Dopper85MD, Harro

Seelaar85PhD, Yolande AL Pijnenburg87MD, Philip Scheltens87MD, Giancarlo Logroscino88MD, Rosa Capozzo88MD, Valeria Novelli90PhD, Annibale A Puca91,92MD, Massimo Franceschi93MD, Alfredo Postiglione94MD, Graziella Milan95MD, Paolo Sorrentino95MD, Mark Kristiansen96PhD, Huei-Hsin Chiang97,98PhD, Caroline Graff97,98MD, Florence Pasquier99MD, Adeline Rollin99MD, Vincent Deramecourt99MD, Florence Lebert99MD, Dimitrios Kapogiannis100MD, UK Brain Expression Consortium, North American Brain Expression Consortium, Luigi Ferrucci4MD, Stuart Pickering-Brown5PhD, Andrew B Singleton3*PhD, John Hardy2°*PhD and Parastoo Momeni1*PhD.

Affiliations 1. Laboratory of Neurogenetics, Department of Internal Medicine, Texas Tech University Health Science Center, Lubbock, Texas, USA 2. Reta Lila Weston Research Laboratories, Department of Molecular Neuroscience, UCL Institute of Neurology, London WC1N 3BG, UK 3. Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA 4. Clinical Research Branch, National Institute on Aging, Baltimore, MD, USA 5. Institute of Brain, Behaviour and Mental Health, Faculty of Medical and Human Sciences, University of Manchester, Manchester, UK 6. Neuroscience Research Australia, Sydney, NSW 2031, Australia 7. University of New South Wales, Sydney, NSW 2052, Australia 8. South Australian Clinical Genetics Service, SA Pathology (at Women's and Children's Hospital), North Adelaide, SA 5006, Australia 9. Department of Paediatrics, University of Adelaide, Adelaide, SA 5000, Australia 10. Memory Clinic of Fundació ACE, Institut Català de Neurociències Aplicades, Barcelona, Spain 11. Hospital Universitari Vall d’Hebron–Institut de Recerca, Universitat Autonoma de Barcelona (VHIR-UAB), Barcelona, Spain 12. Neurology Clinic, University of Brescia, Brescia, Italy 13. Department of Psychiatry, Washington University, St. Louis, MO, USA 14. Hope Center, Washington University School of Medicine, St. Louis, Missouri, USA 15. Department of Pathology and Immunology, Washington University, St. Louis, Missouri, USA 16. NeuroBioGen Lab-Memory Clinic, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy 17. Proteomics Unit, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia Italy 18. Biology of Neurodegenerative Disorders, IRCCS Istituto di Ricerche Farmacologiche "Mario Negri", Milano, Italy 19. University of Milan, Milan, Italy 20. Fondazione Cà Granda, IRCCS Ospedale Maggiore Policlinico, via F. Sforza 35, 20122, Milan 21. Memory Unit, Neurology Department and Sant Pau Biomedical Research Institute, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain 22. Center for Networker Biomedical Research in Neurodegenerative Diseases (CIBERNED), Madrid, Spain 23. Unit of Geriatric Psychiatry, Department of Clinical Sciences, Lund University, Sweden

24. Clinical Memory Research Unit, Department of Clinical Sciences, Lund University, Sweden 25. Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Canada 26. Division of Neurology, University of British Columbia, Vancouver, Canada 27. Institute of Brain, Behaviour and Mental Health, University of Manchester, Salford Royal Hospital, Stott Lane, Salford, M6 8HD, UK 28. Rehabilitation Institute of Chicago, Departments of Physical Medicine and Rehabilitation, Psychiatry, and Cognitive Neurology & Alzheimer's Disease Center; Feinberg School of Medicine, Northwestern University 29. Department of Psychology, Weinberg College of Arts and Sciences, Northwestern University 30. Newcastle Brain Tissue Resource, Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne, NE4 5PL, UK 31. Newcastle University, Institute for Ageing and Health, Campus for Ageing and Vitality, NE4 5PL, Newcastle upon Tyne, UK 32. Institute of Neuroscience, Newcastle University Medical School, Framlington Place, Newcastle upon Tyne, NE2 4HH, UK 33. Biomedical Research Building, Campus for Ageing and Vitality, Newcastle University, Newcastle upon Tyne, NE4 5PL, UK 34. Clinical Psychology Branch, Pisa University Hospital, Pisa, Italy, Laboratory of Clinical Biochemistry and Molecular Biology, University of Pisa, Pisa, Italy 35. Taub Institute, Departments of Psychiatry and Neurology, Columbia University, 630 West 168th Street, P&S Box 16, New York, NY 10032 36. Behavioral Neurology Unit, National Insititute of Neurological Disorders and Stroke, National Insititutes of Health, 10 CENTER DR MSC 1440, Bethesda, MD 20892-1440 37. Neuropathology Dept. Lower Lane, Walton Centre FT, Liverpool, L9 7LJ, UK 38. Neuropathology/Cellular Pathology, Royal Victoria Infirmary, Queen Victoria Road, Newcastle upon Tyne, NE1 4LP 39. Neurogenetics Laboratory, Division of Neurosciences, Center for Applied Medical Research, Universidad de Navarra, Pamplona, Spain 40. Department of Neurology, Clínica Universidad de Navarra, University of Navarra School of Medicine, Pamplona, Spain 41. Neuroepidemiology and Ageing Research Unit, School of Public Health, Faculty of Medicine, The Imperial College of Science, Technology and Medicine, London W6 8RP, UK 42. West London Cognitive Disorders Treatment and Research Unit, West London Mental Health Trust, London TW8 8 DS, UK 43. Department of Psychiatry and Psychotherapy, Technische Universität München, Munich, 81675 Germany 44. Neurology I, Department of Neuroscience, University of Torino, Italy, A.O. Città della Salute e della Scienza di Torino, Italy 45. Tanz Centre for Research in Neurodegenerative Diseases & Department of Medicine, University of Toronto, 6 Queen’s Park Crescent West, Toronto, Ontario, Canada M5S 3H2 46. Cambridge Institute for Medical Research, and the Department of Clinical Neurosciences, University of Cambridge, Hills Road, Cambridge, UK CB2 0XY

47. Division of Neurology V and Neuropathology, Fondazione IRCCS Istituto Neurologico Carlo Besta, 20133 Milano Italy 48. Cambridge University Department of Clinical Neurosciences, Cambridge, CB2 0SZ 49. MRC Cognition and Brain Sciences Unit, Cambridge, CB2 7EF 50. Behavioural and Clinical Neuroscience Institute, Cambridge, CB2 3EB 51. Department of Psychiatry and Psychotherapy, University of Freiburg Medical School, Hauptstr. 5, D- 79104 Freiburg, Germany 52. Department of Molecular Neurology, University Hospital Erlangen, 91054 Erlangen, Germany 53. MRC Prion Unit, Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square 54. Neurologische Klinik und Poliklinik, Ludwig-Maximilians-Universität, Munich, Germany 55. German Center for Neurodegenerative Diseases (DZNE), Munich, Germany 56. University of Pennsylvania Perelman School of Medicine, Department of Neurology and Penn Frontotemporal Degeneration Center, Philadelphia PA USA 57. Neurodegenerative Brain Diseases group, Department of Molecular Genetics, VIB, Antwerp, Belgium 58. Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium 59. Neurorehabilitation Unit, Dept. Of Clinical Neuroscience, Vita-Salute University and San Raffaele Scientific Institute 60. Inserm, UMR_S975, CRICM, F-75013, Paris, France ; UPMC Univ Paris 06, UMR_S975, F-75013, Paris, France ; CNRS UMR 7225, F-75013, Paris, France 61. AP-HP, Hôpital de la Salpêtrière, Département de neurologie-centre de références des démences rares, F-75013, Paris, France 62. Service de Neurologie, Inserm U1079, CNR-MAJ, Rouen University Hospital, France 63. Service de neurologie, CH Saint Brieuc, France 64. Service de neurologie, CHU Nantes, France 65. Department of Neurosciences, Psychology, Drug Research and Child Health (NEUROFARBA) University of Florence, Florence, Italy 66. Danish Dementia Research Centre, Neurogenetics Clinic, Department of Neurology, Rigshospitalet, Copenhagen University Hospital, Denmark 67. Department of Cellular and Molecular Medicine, Section of Neurogenetics, The Panum Institute, University of Copenhagen, Denmark 68. Saarland University Hospital, Department for Psychiatry & Psychotherapy, Kirrberger Str.1, Bld.90, 66421 Homburg/Saar, Germany 69. Saarland University, Laboratory for Neurogenetics, Kirrberger Str.1, Bld.90, 66421 Homburg/Saar, Germany 70. University Regensburg, Department of Psychiatry, Psychotherapy and Psychosomatics, Universitätsstr. 84, 93053 Regensburg, Germany 71. Luxembourg Centre For Systems Biomedicine (LCSB), University of Luxembourg, 7, avenue des Hauts- Fourneaux, 4362 Esch-sur-Alzette, Luxembourg 72. Dementia Research Centre, Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, WC1N 3BG 73. University of Cambridge, Department of Clinical Neurosciences, John Van Geest Brain Repair Centre, Forvie Site, Robinson way, Cambridge CB2 0PY

74. MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, School of Medicine, Cardiff CF14 4XN 75. German Center of Neurodegenerative Diseases-Tübingen Paul-Ehrlich Straße 15 72076 Tübingen, Germany 76. Salford Royal Foundation Trust, Faculty of Medical and Human Sciences, University of Manchester 77. Institute of Brain, Behaviour and Mental Health, The University of Manchester 27 Palatine Road, Withington, Manchester, M20 3LJ, United Kingdom 78. Regional Neurogenetic Centre, ASPCZ, Lamezia Terme, Italy 79. Department of Neuroscience, Mayo Clinic Jacksonville, 4500 San Pablo Road, Jacksonville, FL 32224 80. Department of Neurology, Mayo Clinic Jacksonville, 4500 San Pablo Road, Jacksonville, FL 32224 81. Department of Neurology, Mayo Clinic Rochester, 200 1st street SW Rochester MN 5905 82. Department of Pathology, Mayo Clinic Rochester, 200 1st street SW Rochester MN 5905 83. Department of Neurology, Box 1207, University of California, San Francisco, San Francisco, CA 94143 84. Memory and Aging Center, Department of Neurology, University of California, San Francisco, CA 94158 85. Department of Neurology, Erasmus Medical Centre, Rotterdam, The Netherlands 86. Department of Medical Genetics, VU university Medical Centre, Amsterdam, The Netherlands 87. Alzheimer Centre and department of neurology, VU University medical centre, Amsterdam, The Netherlands 88. Department of Basic Medical Sciences, Neurosciences and Sense Organs of the "Aldo Moro" University of Bari, Italy 89. Department of Medical and Molecular Genetics, King¹s College London, 8th Floor, Tower Wing, Guy¹s Hospital, London SE1 9RT, UK 90. Department of Molecular Cardiology, IRCCS Fondazione S. Maugeri, Pavia, Italy 91. Cardiovascular Research Unit, IRCCS Multimedica, Milan, Italy 92. Department of Medicine and Surgery, University of Salerno, Baronissi (SA), Italy 93. Neurology Dept, IRCCS Multimedica, Milan, Italy 94. Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy 95. Geriatric Center Frullone- ASL Napoli 1 Centro, Naples, Italy 96. UCL Genomics, Institute of Child Health (ICH), UCL, London, UK 97. Karolinska Institutet, Dept NVS, KI-Alzheimer disease research center, Novum, SE-141 86, Stockholm, Sweden 98. Dept of Geriatric Medicine, Genetics Unit, M51, Karolinska Universtiy Hospital, SE-14186, Stockholm 99. Université Lille Nord de France, CHU 59000 Lille, France 100. National Institute on Aging (NIA/NIH), 3001 S. Hanover St, NM 531, Baltimore, MD, 21230

’Contributed equally; °Corresponding author: John Hardy PhD, FMedSci FRS Reta Lila Weston Research Laboratories, Departmental Chair, Department of Molecular Neuroscience, UCL Institute of Neurology, London WC1N 3BG, England. Phone: +44 (0) 207 679 4297; Fax: +44 (0) 207-833-1017. Email: [email protected]; *Joint last authors.

Summary Background Frontotemporal dementia (FTD) is a complex disorder characterized by a broad range of clinical manifestations, differential pathological signatures and considerable genetic variability. To date, mutations in three genes – MAPT, GRN, and C9orf72 – have been associated with FTD. In the current study we sought identifying novel genetic risk loci associated with disease.

Methods We performed a 2-stage genome wide association study (GWAS) on clinical FTD analyzing a total of 3,526 FTD cases and 9,402 controls with European ancestry. We conducted separate association analyses for each FTD subtype (behavioural variant FTD [bvFTD], semantic dementia [SD], progressive non-fluent aphasia [PNFA], and FTD overlapping with motor neuron disease [FTD-MND]) and then meta- analyzed the entire dataset in discovery phase (2,154 cases vs. 4,308 controls). We carried forward replication of the novel suggestive loci in an independent sample series (1,372 cases vs. 5,094 controls) and then performed joint phase and brain e/mQTL (expression/methylation quantitative trait loci) analyses for the associated and suggestive SNPs.

Findings We identified novel associations exceeding the genome wide significance threshold (p- value<5x10-8) that encompassed the HLA locus at 6p21·3 in the entire cohort. We also identified a potential novel locus at 11q14, encompassing RAB38/CTSC for the bvFTD subtype. Analysis of expression and methylation quantitative trait loci (e/mQTL) data suggested that these loci might affect expression and methylation in-cis.

Funding Intramural funding from the National Institute of Neurological Disorders and Stroke (NINDS) and National Institute on Aging (NIA), the Wellcome/MRC Centre on Parkinson’s disease, Alzheimer’s Research UK (ARUK), and Texas Tech University Health Sciences Center (TTUHSC) office of the Dean.

Introduction Frontotemporal dementia (FTD) is the second most common form of young-onset dementia after Alzheimer’s disease (AD) and represents ~10-20% of all dementias worldwide.1 FTD occurs in approximately three-15/100,000 individuals aged mid to late 50s or early 60s.2 The disease has an insidious onset; it is familial in 30-50% of cases and affects men and women almost equally.3 The main clinical syndromes are the behavioural (bvFTD)1,4 and the language variants (semantic dementia [SD] and progressive nonfluent aphasia [PNFA]).1,5 There is also overlap with motor neuron disease (FTD-MND), and atypical parkinsonian disorders.3 The molecular pathology is heterogeneous and based on the type of neuronal lesions and protein inclusions: ≥40% of cases have tau pathology (FTLD-tau: frontotemporal lobar degeneration with tau inclusions), ~50% have TDP-43 (TAR-DNA binding protein 43) pathology (FTLD-TDP),6 and the remaining ≤10% fused in sarcoma (FUS) (FTLD-FUS) or ubiquitin/p62 positive inclusions (FTLD-UPS [ubiquitin proteasome system]).7 Mutations in three main genes are commonly associated with FTD: the microtubule associated protein tau (MAPT),8 granulin (GRN),9,10 and C9orf72.11- 15 Mutations in the charged multivesicular body protein 2B (CHMP2B), the valosin containing protein (VCP), and ubiquilin 2 (UBQLN2) genes are rare causes of disease.13,16 A previous genome-wide association study (GWAS) on neuropathologically confirmed FTLD-TDP (515 cases vs. 2,509 controls) identified TMEM106B as a disease risk factor.17

Herein we present a larger GWAS on clinical FTD and report results for the discovery, replication and joint phase analyses, as well as for assessment of effect on expression and methylation quantitative trait loci (QTL) exerted by associated and/or suggestive SNPs. The aim of this study was to identify novel genetic risk loci associated with frontotemporal dementia and its subtypes.

Materials and Methods

Cases ascertainment Forty-four international research groups (Supplementary Table S1; webappendix pp 1-2) contributed samples to this 2-stage (discovery and replication phases) GWAS on clinical FTD. Appropriate informed consent for cases and controls was obtained at each individual site and every participating group provided consent for their use for the purposes of this study. The cases included in discovery phase were collected by mid 2010 and were diagnosed according to the Neary criteria1 for FTD; cases included in replication phase were collected between 2011 and early 2013: the majority of the samples were diagnosed according to the Neary criteria1 whereas the most recent cases were diagnosed according to the revised criteria for bvFTD4 and SD/PNFA5 at each collaborative site. For each case the diagnosis was made by either a neurologist with an interest in FTD or (the minority) by pathological diagnosis. To cover the most relevant FTD clinical signatures, patients diagnosed with bvFTD, SD, PNFA, and FTD-MND18 were included in the study. All language cases were reviewed to exclude cases of the logopenic variant of primary progressive aphasia,5 the majority of which are associated with Alzheimer’s disease pathology. Samples were obtained from North America (US and Canada), UK, France, Netherlands, Belgium, Germany, Denmark, Sweden, Spain and Italy and were of confirmed European ancestry.

DNA was collected at the three Institutions leading this project: the Department of Molecular Neuroscience at the University College of London (UCL), the Laboratory of Neurogenetics of the National Institute on Aging at the National Institutes of Health (NIH), and the Laboratory of Neurogenetics at the Texas Tech University Health Sciences Center (TTUHSC). All samples were de-identified and stored with a specific coded ID. Each DNA sample was evaluated for quality through gel electrophoresis and concentrations were evaluated via spectrophotometer (Nanodrop) or fluorometer (Qubit) (see further below). Non-overlapping cases were genotyped at the Laboratory of Neurogenetics of the National Institute on Aging at the NIH (40%) and at the core facility at the Institute of Child Health at UCL (60%). Standardized clinical, pathological and genetic information for each case was collected from all the collaborating groups (Supplementary Table S2; webappendix pp 3). Sporadic cases along with probands from FTD families were included in the study. Carriers of mutations in MAPT and GRN were excluded from the study. Individuals with C9orf72 expansions were not excluded because this locus was identified subsequent to sample collection. During the discovery phase we collected a total of 3,581 cases; after material quality check (QC) 2,559 cases were genotyped. Subsequently, after genotyping data QC and detailed assessment of the clinical diagnosis, 2,154 cases were used for association analysis (Table 1a). During the replication phase we collected a total of 1,993 cases; after material QC 1,581 cases were genotyped. Subsequently, after genotyping data QC and detailed assessment of the clinical diagnosis, 1,372 cases were used for the replication analysis (Table 1a). In total, 3,526 FTD samples that survived quality control (QC) were analyzed in this study (Table 1a).

Controls ascertainment Normal controls for the discovery phase were taken from studies previously conducted at either the Laboratory of Neurogenetics at the NIH or at the UCL. Controls were matched based on population ancestry and genotyping platform. Aggregate data for control samples were merged based on overlapping SNPs. The selected 7,444 control samples originated from the US, UK, Italy, Germany, France, Sweden, and the Netherlands and were used as controls in previous GWAS; 19 all had given consent for their samples to be used as controls. All were free of neurologic illness at time of sampling but most controls had not been screened for the absence of a family history of FTD. For each case, at least 2 controls were matched based on compatibility of genetic ancestry estimates by principal components analysis (PCA) to accommodate the lack of precisely matched clinical controls. Eventually 4,308 controls survived QC. The genotyping of controls for the replication phase was performed at the Laboratory of Neurogenetics of the National Institute on Aging at the NIH (90%) and at the core facility at the Institute of Child Health at UCL (10%). All controls used in the replication phase were collected from the groups participating in the study (n=5,094 survived QC) and were from the following ancestry backgrounds: US (European/American), UK, Italy, France, Germany, Sweden, Spain, and the Netherlands.

DNA Quality Control For each sample, a total amount of 2μg of DNA extracted either from blood or brain at each collaborative site was collected (whole genome amplified DNA samples were excluded).

Samples were securely stored in -20°C freezers. Each sample was first screened for integrity by means of gel electrophoresis on 1% agarose gel and purity, as well as concentration were analyzed by

8 spectrophotometric (Nanodrop, Wilmington, DE, USA) or fluorometric (Qubit, Life Technologies, Grand Island, NY, USA) quantification. The same procedure was implemented at UCL, NIH and TTUHSC.

Genotyping platform Samples and controls included in discovery phase were genotyped using Illumina human 370K-, 550K-, 660K-Quad Beadchips and Omni Express chips. Illumina NeuroX custom chips were used for all samples and controls included in replication phase genotyping. The NeuroX chip is a partially custom designed chip that specifically targets the main loci associated with a number of different neurological disorders obtained from published or available GWAS and/or whole exome sequencing data. The NeuroX chip holds ~267K SNPs of which 3,759 were FTD specific being selected from SNPs that reached p- values<1x10-4 during the discovery phase of the study. These SNPs were tag SNPs based on European ancestry linkage disequilibrium (LD) patterns based on the most recent data for samples of European ancestry from the 1000 Genomes project.20 For all GWAS significant hits and candidate SNPs, 5 LD-based proxies or technical replicates were included on the array per locus, tagging associations within +/- 250 kb and r2 >0·5 from the most strongly associated proximal SNP. To replicate each locus, we picked the tag SNP most significant in the discovery phase a priori. If no LD-based proxies were available, technical replicates were included. All genotyping arrays (discovery phase + replication phase) were assayed on the Illumina Infinium platform (Illumina, San Diego, CA, USA) at the Laboratory of Neurogenetics of the National Institute on Aging at NIH and at the core facility at the Institute of Child Health (ICH) at the UCL. All genotypes for this project were called centrally using Illumina Genome Studio and all 3,759 SNPs of interest for FTD were manually examined to ensure high quality genotype clusters prior to data export.

Statistical methods and quality control

Discovery phase Standard QC for GWAS data was undertaken prior to association analyses. In brief, for the discovery phase: overlapping SNPs across all Illumina arrays used in this project were extracted. This was done as a means of dealing with the low numbers of matched cases and controls per study site or chip type to facilitate the FTD subtype analyses. We attempted to maximize sample size for the subtype analyses by pooling as many possible samples while sacrificing some array content, leaving a total of 228,189 autosomal SNPs as a basis for imputation after the quality control described below was completed. Possible gender mismatch samples were excluded by evaluating X heterozygosity. Samples with call rate >95% and SNPs with minor allele frequency (MAF) >1% were filtered and included in the analyses. Hardy-Weinberg equilibrium (HWE) was calculated (exclusion at p-values <1x10-5). Non- random missingness per SNP by case-control status with exclusion at p-values <1x10-5 and non-random missingness per SNP by haplotype at p-values for exclusion <1x10-5 were assessed. Presence of relatedness was evaluated by identifying and excluding 1st degree relatives (through identity by descent [IBD] for any pairwise with an estimate <0·125) and European ancestry was verified by PCA compared to HapMap3 populations, with European ancestry ascertained at values for the first two eigenvectors less than six standard deviations from the population mean for the combined CEU and TSI reference samples.21 After preliminary quality assessment, PCA as implemented in EIGENSTRAT22 was used to evaluate matching between cases and controls based on all available cases and controls. Custom coding

9 in R was used to match cases to controls. Each subtype (bvFTD, SD, PNFA and FTD-MND) was treated as separate groups in which the two most genetically similar unique controls per case were selected based on eigenvectors 1 and 2. This was carried out to compensate for a lack of precisely matched controls at recruitment / study design. In this aspect, matched controls were unique per case and non-redundant across subtype datasets. Thus, cases and controls were matched for each subtype (bvFTD, SD, PNFA and FTD-MND) based on similarity of the first two eigenvectors from PCA and did not overlap across subtypes. Logistic regression was used based on imputed dosages to assess the association between each SNP and any of the FTD subtypes, adjusting for eigenvectors 1 and 2 from PCA as covariates. Eigenvectors were generated separately for each subtype, as in the overall sample pool, parameter estimates for the first 2 were associated with case status at p-values < 0·05. Fixed effects meta-analyses were performed to combine results across subtypes and quantify heterogeneity across subtypes. Genomic inflation was minimal across subtypes and in the meta-analysis across subtypes (lambda <1·05), therefore we did not use genomic control (see Supplementary Figure SF1, webappendix pp 4, for quantile-quantile plots and lambda values per discovery phase analysis). SNPs were imputed to August 2010 release of the 1000 genome haplotypes using default settings of minimac [http://genome.sph.umich.edu/wiki/Minimac] and were excluded if their MAF was <0·01 or imputation quality (Rsq) was <0·30 across all samples, leaving 6026385 SNPs for analyses.

Replication phase For the replication phase, standard QC was performed as for the discovery phase with slight adjustments to account for the bias in NeuroX array content (candidate neurological/neurodegenerative disease SNPs and exonic content). Standard content variants included on the NeuroX array that were used for sample QC were called using a publicly available cluster file based on over 60,000 samples.23 For QC, variants with GenTrain scores >0·70 (indicative of high quality genotype clusters) were extracted first to calculate call rates. Samples with call rates <95% were excluded, as were samples whose genetically determined sex conflicted that from the clinical data and samples exhibiting excess heterozygosity. Next, SNPs overlapping with HapMap Phase 3 samples were extracted from the previous subset and pruned for LD (SNPs excluded if r2 >0·50 within a 50 SNP sliding window), as well as SNPs with MAF <5%, HWE p-values <1x10-5, and per SNP missingness rates >5%. At this stage, pairwise IBD filtering was used to remove samples that were cryptically related and PCA was used to identify samples to be excluded due to genetic ancestry not consistent with European descent based on comparisons with HapMap Phase 3 reference populations. For replication analyses and due to an effort to maximize the limited power of this phase compared to the discovery phase, analyses of each subtype included all control samples available adjusting for the first five eigenvectors only from PCA as covariates in the logistic regression model. No other adjustments were implemented. In addition, we pooled the individual genotypes from different subsets together in the replication phase to help increase statistical power.

Expression and methylation quantitative trait loci (QTL)

UK Brain Expression Consortium (UKBEC)

Sample Collection Brain samples originating from 134 control individuals were collected by the Medical Research Council (MRC) Sudden Death Brain and Tissue Bank,24 Edinburgh, UK (n=100), and the Sun Health Research Institute (SHRI) Brain Donation Program25 an affiliate of Sun Health Corporation, USA (n=34). All individuals were confirmed to be neuropathologically normal by histology performed on sections prepared from paraffin-embedded brain tissue blocks and the diagnosis was determined by a consultant neuropathologist. All samples had fully informed consent for retrieval and were authorized for ethically approved scientific investigation (Research Ethics Committee number 10/H0716/3). In this study we specifically assessed expression in frontal cortex tissue.26-28

RNA isolation and processing of samples using Affymetrix Exon 1·0 ST Arrays Total RNA was isolated from human post-mortem brain tissues using the miRNeasy 96 well kit (Qiagen, UK). The quality of total RNA was evaluated by the 2100 Bioanalyzer (Agilent, UK) and RNA 6000 Nano Kit (Agilent, UK) before processing with the Ambion® WT Expression Kit and Affymetrix GeneChip Whole Transcript Sense Target Labeling Assay, and hybridization to the Affymetrix Exon 1.0 ST Arrays following the manufacturers’ protocols. Hybridized arrays were scanned on an Affymetrix GeneChip® Scanner 3000 7G and visually inspected for hybridization artefacts. Further details regarding tissue collection, RNA isolation, quality control and processing have been previously reported.29

All arrays were pre-processed using Robust Multi-array Average (quantile normalisation, summary by median polish) algorithm30 in Affymetrix Power Tools 1.14.3 software (http://www.affymetrix.com/partners_programs/programs/developer/tools/powertools.affx). After re- mapping the Affymetrix probesets onto human genome build 19 (GRCh37) as documented in the Netaffx annotation file (HuEx-1_0-st-v2 Probeset Annotations, Release 31), we restricted analysis to probesets that had gene annotation, contained at least 3 probes that were uniquely hybridized to the genome and without polymorphisms (MAF > 1% in the European panel of the March 2012 release of 1000 Genomes) within the probe sequences.31 Gene expression data is available from Gene Expression Omnibus under the accession number GSE46706.

DNA extraction, genotyping and imputation Genomic DNA was extracted from sub-dissected samples (100–200 mg) of human post-mortem brain tissue using Qiagen’s DNeasy Blood & Tissue Kit (Qiagen, UK). Samples from every individual were run on two different genotype chips: the Illumina Infinium Omni1-Quad BeadChip and the ImmunoChip, a custom genotyping array designed for the fine-mapping of auto-immune disorders.32 The BeadChips were scanned using an iScan (Illumina, USA) with an AutoLoader (Illumina, USA). GenomeStudio v.1.8.X (Illumina, USA) was used for analysing the data and generating SNP calls.

Prior to imputation, standard quality controls were conducted in each array type. This included removal of individuals suspected to be of non-European ancestry (3 removed) and sample call rate < 95% (none removed). Standard quality control on the genotype data included removal of CNV and indel markers

11 and SNPs with either call rate < 95%, p-value of deviation from Hardy-Weinberg Equilibrium < 0·0001 or less than 2 heterozygotes present or mismatching alleles with the 1000 Genomes even after strand flipping or symmetric SNPs with ambiguous allele frequency.

After standard quality controls, genotyped SNPs from both arrays were combined and imputed using MaCH33, 34 and minimac (http://genome.sph.umich.edu/wiki/Minimac) using the 1000Genomes (March 2012). We used the resulting ~5·8 million SNPs and ~570 thousand indels with good post-imputation quality (r2 > 0·50) and minor allele frequency of at least 5% in subsequent analyses.

North American Brain Expression Consortium (NABEC)

Sample collection Frontal cortex samples originating from 399 neuropathologically-confirmed control individuals were collected as previously described.32, 35 Briefly the samples originated from the University of Maryland Brain Bank, Baltimore (n=207), Sun Health Research Institute (n=52, non-overlapping with UKBEC), Baltimore Longitudinal Study of Aging (n=20), University of Miami (n=16), the Department of Neuropathology of John Hopkins University (n=9) and the Medical Research Council (MRC) Sudden Death Brain and Tissue Bank (n=95, subset of UKBEC). This study was approved by the appropriate institutional research ethics board.

RNA isolation and processing of samples using Illumina Human HT12-v3 Arrays Total RNA was extracted from sub-dissected samples (100–200 mg) of human post-mortem brain tissue using a glass-Teflon homogenizer and 1mL TRIzol (Invitrogen, Carlsbad, CA) according to the manufacturers’ instructions. RNA was biotinylated and amplified using the Illumina® TotalPrep-96 RNA Amplification Kit and directly hybridized onto Human HT12 Expression BeadChips (Illumina Inc., USA) in accordance with the manufacturer’s instructions.

Expression data were analysed using the Gene Expression Module 3.2.7 within Illumina® BeadStudio. Raw intensity values for each probe were transformed using the cubic spline normalization method and then log2 transformed for mRNA analysis. We re-mapped the annotation for probes according to ReMOAT36 on the human genome build 19 and then restricted the analysis to genes that were reliable, uniquely hybridized and were associated with gene descriptions. Gene expression is available from Gene Expression Omnibus under the accession number GSE36192.

DNA isolation and processing of samples using Illumina Human Methylation27 arrays The CpG methylation in cerebellum and frontal cortex was determined in a subset of the NABEC dataset (n=292). Genomic DNA was phenol–chloroform extracted and quantified on the Nanodrop1000 spectrophotometer prior to bisulfite conversion. Bisulfite conversion of 1 µg of genomic DNA was performed using Zymo EZ-96 DNA Methylation Kit as per the manufacturer's protocol. CpG methylation status of at 27,578 CpG dinucleotides at 14,495 genes was determined using Illumina Infinium HumanMethylation27 BeadChip, as per the manufacturer's protocol. Data were analyzed in BeadStudio software (Illumina Beadstudio v.3.0). The threshold call rate for inclusion of samples in analysis was 95%. Quality control of sample handling included comparison of genders reported by the brain banks with the gender of the same samples determined by analyzing methylation levels of CpG sites on the X

12 chromosome. Beta values were extracted for sites on chromosome X and loaded into the TM 4 MeV tool. These data were then clustered by sample. Based on the methylation levels for chromosome X loci, these data split into two primary groups based on gender. Calls generated by this method were then compared with sample information reported by the brain bank. Samples where genders did not match between brain bank and methylation data were excluded from our analyses. The methylation data is available from Gene Expression Omnibus under the accession number GSE36194.

DNA extraction, genotyping and imputation The DNA extraction and imputation protocol is similar to that employed in UKBEC. The individuals not overlapping with UKBEC genotyped on Illumina Infinium HumanHap550 v3 (Illumina, USA). The SNPs that pass quality control and common to both UKBEC and non-UKBEC individuals were extracted for imputation and approximately 5·3 million SNPs were available after imputation and quality control. eQTL analyses The SNP dosage was analyzed assuming an additive genetic model using linear regression adjusting for covariates of gender, age at death, post mortem interval (PMI), brain bank, batch in which preparation or hybridization were performed (and for the first two principal components of population stratification in NABEC dataset). The analyses were conducted using MACH2QTLv1.11 (http://www.sph.umich.edu/csg/abecasis/MaCH/download/) for NABEC and using MatrixEQTL37 and R (http://www.R-project.org/) for UKBEC. We tested for association with all probes and probesets located within +/- 1MB of each SNP.

Role of the funding source The sponsors of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report. No pharmaceutical company or other agency paid to write this article. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication.

Results In discovery phase, we analyzed 2,154 cases (Table 1a) and 4,308 controls. We first conducted separate association analyses for each subtype (bvFTD, SD, PNFA, and FTD-MND; Table1b) and then meta- analyzed the entire dataset.

The meta-analysis revealed 29 SNPs (Supplementary Table S3; webappendix pp 5) exceeding genome- wide significance (p-value <5x10-8) at the HLA locus (6p21·3), encompassing the butyrophilin-like 2 (MHC class II associated) gene (BTNL2) and the major histocompatibility complex, class II, DR alpha (HLA-DRA) and DR beta 5 (HLA-DRB5) (Figure 1a; Table 2). To identify susceptibility loci for the bvFTD subtype we analyzed 1,377 cases (Table 1b) and 2,754 controls. Two non-coding SNPs at 11q14, locating to intron 1 of the gene RAB38, member RAS oncogene family (RAB38) (rs302652) and encompassing RAB38 and cathepsin C (CTSC) (rs74977128), passed the genome-wide significance threshold (Figure 1b; Table 2). Similarly we carried out analyses on the other subtypes (Table 1b): 308 SD vs. 616 controls, 269 PNFA vs. 538 controls, and 200 FTD-MND vs. 400 controls. No SNP reached genome-wide significance in either

13 subtype, probably due to a relatively small sample size. However, several SNPs (Supplementary Table S4; webappendix pp 6-26) showed suggestive associations (p-values between 10-6 and 10-7) (Figure 1c-d-e) and deserve further investigation in future screenings. In replication phase we analyzed 1,372 cases (Table 1a) along with 5,094 controls. We evaluated the associated SNPs at 6p21·3 (rs9268877, rs9268856, and rs1980493) in the whole replication cohort with the following results: rs9268856 showed a p-value=1·4x10-2 with OR=0·878, rs1980493 showed a p-value=2·0x10-2 with OR=0·85, and rs9268877 showed a p-value=1·04x10-1 with OR=1·080 (Table 2). The surrogate/proxy SNPs assessed for replication at 11q14 in 690 bvFTD cases revealed the following results: rs302668 showed a p- value=4·1x10-2 with OR=0·877 (r2 [correlation coefficient that indicates the predictive LD between two loci]=0·65) and rs16913634 showed a p-value=7·1x10-1 with OR=0·964 (r2=0·54) (Table 2). Combined analyses of discovery and replication phases revealed genome-wide significant association at 6p21·3 for all SNPs: rs9268877 (p-value=1·05x10-8, OR=1·204), rs9268856 (p-value=5·51x10-9, OR=0·809), and rs1980493 (p-value=1·57x10-8, OR=0·775) (Table 2). Joint p-values of the SNPs at 11q14 only revealed suggestive association for rs302668 (p-value=2·44X10-7, OR= 0·814) (Table 2) possibly because of decreased power due to proxy-based replication (r2=rs302652 to rs302668=0·65).

We then evaluated biological relevance for the novel potential loci in human brain cortex tissues assayed for genome-wide expression and methylation. There was no eQTL in our dataset, however, assessment of the Zeller et al dataset38 revealed a cis-eQTL (p=5·05x10-32, Supplementary Table S5; webappendix pp 27) at 11q14 for rs302652 (chr11:87894881, risk allele T) causing a decreased expression of RAB38 (Illumina ILMN_2134974 located on chr11:87846656-87846705) in monocytes. These data suggest a role in transcriptional processes in –cis for this SNP. Further, we identified significant cis-mQTL at 6p21·3 after multiple test correction for rs1980493 (risk allele T) that associated with changes in the methylation levels related to HLA-DRA in the frontal cortex (p-value=2·17x10-8) (Table 3).

In order to evaluate potential genetic overlap between FTD and closely related forms of neurodegenerative diseases we selected relevant SNPs for candidate loci and analysed them in our dataset. This analysis included published association studies for ALS,39 PSP/CBD,40 AD41 and FTLD-TDP.17 In addition, we assessed whether the two loci identified through this study had also been reported previously in other studies on neurological disorders.

C9orf72 locus (ALS): the SNP rs3849942 (effect allele A) achieved a p-value of 2·12x10-6 and an OR of 1·957 in the FTD-MND subtype consistent with our post hoc analyses (~23% of expansion carriers among this subtype) (Table 4; Supplementary Table S6, webappendix pp 28). Association was modest in bvFTD (p-value=7·38x10-3, OR=1·155) as well as in the entire discovery cohort (p-value=4·38x10-4, OR=1·166), while there was no evidence for association in the SD or PNFA subtypes (Table 4). These results confirm that the C9orf72 locus associates mainly with FTD-MND and to a lesser extent with bvFTD (Supplementary Table S6; webappendix pp 28).

MAPT locus (PSP/CBD): the SNPs rs242557 and rs8070723 (effect alleles G and A respectively)40 reached modest p-values between 10-3 and 10-4 only in the entire cohort, and in the bvFTD and PNFA subtypes (rs8070723 only; Table 4). The effect was small in our study although in the same direction as in the

GWAS for progressive supranuclear palsy (5·4640 vs. ~1·2-1·4 [our study]; Table 4). These results reflect the fact that we excluded all known chromosome 17 mutations carriers and that tau pathology is a less common feature of sporadic FTD.

TOMM40/APOE locus (AD): the SNP rs2075650 (effect allele G) reached a p-value of 8·81x10-7 in the entire dataset and 1·37x10-6 in bvFTD, whereas in the SD, PNFA, and FTD-MND subtypes p-values were in the range of 10-1-10-2 (Table 4). Several AD-GWAS reported association with the minor allele of this SNP with OR>2·5,41 whilst in our study the OR was ~1·3 (Table 4). This suggestive association may reflect clinical overlap (~15%) between clinically diagnosed FTD and AD cases.42

TMEM106B locus (FTLD-TDP): we assessed the three associated SNPs reported by Van Deerlin et al.17 (rs1990622, effect allele A; rs6966915, effect allele C; rs1020004, effect allele T). All achieved modest p- values in the entire dataset with lowest p-values in the range of 10-2-10-3 only in the bvFTD subtype (Table 4). The original work17 was performed on autopsy-confirmed FTLD-TDP cases whereas our cohort is mainly clinically defined. In addition, the previous study included a considerable number of GRN mutation carriers which frequently present with bvFTD;17 in our study GRN mutation carriers were excluded. Biochemical evidence has suggested TMEM106B to be directly related to GRN metabolism,13 thus we regard to our data as a limited replication of the original finding.

Finally, the RAB38 locus previously showed suggestive association in multiple sclerosis (MS),43 whilst the HLA locus was reported associating with MS,44,45 Parkinson’s disease (PD)19,46 and AD.47 None of the SNPs reported in these studies, and that were assessed in our dataset (Table 4),43-46 showed association with FTD, probably suggesting that different risk haplotype sub-structures at the same loci associate with distinctive phenotypes.

Discussion Frontotemporal dementia is characterized by a broad range of clinical manifestations, differential pathological signatures and considerable genetic variability implying to complex disease mechanisms.15 In the search for novel disease risk loci associated with FTD we have performed an extensive GWAS on a large cohort of mainly clinically diagnosed FTD samples of European ancestry. It needs to be acknowledged that a number of limitations may apply to this study. Given phenotype heterogeneity of FTD and considering that it is a rare neurodegenerative disorder (low prevalence),2 testing the hypothesis “common variant – common disease” for diseases of this kind is challenging and clearly benefits from large sample sizes. In addition, our study may indicate association with specific loci without necessarily implying causality; low heritability due to common variability may also apply. However, importantly, the QQ plots and associated lambda values (Supplementary Figure SF1, webappendix pp 4) conformed to GWAS standards, supporting confidence in the final results, eventually.

15 suggestive for the bvFTD subtype, and 6p21·3, encompassing the HLA locus was significant for the entire cohort.

RAB3848 encodes the transmembrane protein RAB38 that is expressed in the thyroid, elements of the immune system, and in the brain (http://www.genecards.org/cgi-bin/carddisp.pl?gene=RAB38; accessed August 2013). From a functional perspective, RAB38 has been shown to mediate protein trafficking to lysosomal-related organelles and maturation of phagosomes.49,50 CTSC is a lysosomal cysteine- proteinase which participates in the activation of serine proteinases in immune/inflammatory cells that are involved in immune and inflammatory processes including phagocytosis of pathogens and local activation and deactivation of inflammatory factors (OMIM: #602365). Of note, the SNP rs302652 at the RAB38/CTSC locus shows an eQTL in monocytes38 associated with decreased expression of RAB38, possibly indicating that a decreased function of RAB38 may be the mechanism by which the association at this locus is mediated. Both RAB38 and CTSC are implicated in lysosomal biology and an association with lysosomal and autophagic processes in FTD was previously suggested in two studies on GRN51 and TMEM106B.52 Interestingly, a role for the autophagy has been also shown in PD.53 Our data will need to be replicated in other FTD cohorts in follow up studies (e.g. fine mapping studies) to support the inference to be made that lysosomal biology and autophagy may be involved in the etiology of FTD.54

The genetic association that we identified with the HLA locus supports the notion of a link between FTD and the immune system. Our mQTL data revealed that risk at this locus significantly associates with cis- changes in methylation levels of HLA-DRA in the frontal cortex. HLA associations have been previously reported in AD,47 PD19,46 as well as classically in MS.44,45 In addition, a general involvement of the innate and the adaptive immune responses has been suggested in the pathogenesis of neurodegenerative diseases,55,56 supporting the notion that the immune system plays an important role within the spectrum of neurological disorders.

Our current work represents a foundation for future studies aimed at replicating these results and at shedding light on the functional basis of FTD. In addition, our data indicate that common pathways and processes may underlie different forms of neurodegenerative disorders, including AD, PD, MS and FTD. Exploring the possibility of developing therapeutic measures targeting general damage responses may hold promise, provided further replication and validation, for the development and implementation of treatment options for these neurological disorders, including FTD.

Panel: Research in context

Systematic review The groups participating in this project are all currently active in the research of neurodegenerative diseases, including frontotemporal dementia. To retrieve information on frontotemporal dementia we searched PubMed for the most relevant published work available on this subject as milestone research articles and review articles using the following terms: FTD and genetics, and FTD and review. 1,4,5,8-17,54 We compared our results to a number of previously published genome wide association studies. There was only one directly relevant study that investigated a pathologically defined subtype of FTD (FTLD- TDP).17 The other studies concerned related diseases such as ALS39, AD41,47, PSP/CBD40 , MS43-45 and

PD.19,46 In our current study, we analyzed a total of 3,526 (after QC) FTD samples obtained from more than 40 international research groups and we carefully selected those samples eligible for genotyping and those to be included in the analyses to generate our association data. Samples and genotyping data were rigorously filtered through high standard QC steps to assess diagnosis, DNA quality and genotyping output data quality (see Material and Methods section). In this association study all genotyping data have been generated and analyzed within the consortium.

Interpretation This study is the first GWAS on clinical frontotemporal dementia. Given the complexity and heterogeneity of the disease, to date, only three main genes are known to explain a small proportion of cases and, most importantly, not much is known about the mechanisms that influence pathogenesis, i.e. the mechanisms underlying the development of this disorder. Our study suggests that common variability in loci that point to immune processes, and possibly lysosomal biology and autophagy, is involved in the pathobiology of the disease. These findings represent a basis for future replication and functional studies.

Authors contribution JH, PM, ABS, MAN, RF and JDR designed the study. JDR, RF and JH performed clinical quality control. RF coordinated sample collection, received samples at UCL and TTUHSC and performed material QC for discovery and replication phases. DGH received samples at NIH and coordinated material QC at NIH. JDR, JBJK, CDS, PRS, WSB, JRH, GMH, OP, LB, ET, EH, IH, AR, MB BB, AP, LB, GB, RG, GF, DG, ES, CF, MS, JC, AL, RB, MLW, KN, CN, IRAM, GYRH, DMAM, JG, CMM, JA, TDG, IGM, AJT, PP, EDH, EMW, AB, EJ, MCT, PP, CR, SOC, EA, RP, JDS, PA, AK, IR, ER, LP, ER, PStGH, ER, GR, FT, GG, JBR, JCMS, JU, JC, SM, AD, VMVD, MG, JQT, JvdZ, TVL, CVB, WD, MC, SFC, ILB, AB, DH, VG, MV, BN, SS, SB, IP, JEN, LEH, MR, BI, MM, GG, SP, WG, MNR, NCF, JDW, MGS, HM, PR, PH, JSS, AG, AR, SR, ACB, RM, FF, CC, LB, MA, MG, MEC, NS, RR, MB, DWD, JEP, NRGR, RCP, DK, KAJ, BFB, WWS, BLM, AMK, HR, JCvS, EGPD, HS, YALP, PS, GL, RC, VN, AAP, MF, AP, GM, PS, HHC, CG, FP, AR, VD, FL, DK, LF, SPB collected and characterized samples at the respective sites. MK was responsible for genotyping at ICH. JH, PM, ABS and SPB provided funding for this study. JH, PM and ABS supervised the study. MAN performed statistical and association analyses. RF, MAN and JH analysed and interpreted the data. AR helped in the interpretation of the e/mQTL data. RF, MAN, JH and PM wrote the first draft of the manuscript. All other co-authors participated in manuscript preparation by reading and commenting the manuscript prior submission.

' RF, DGH, MAN and JDR contributed equally. * ABS, JH and PM joint last authors.

Conflicts of interest The following authors declare no actual or potential competing financial interests: RF, DGH, MAN, JDR, AR, JBJK, CDS, WSB, GMH, JRH, OP, LB, ET, EH, IH, AR, MB, BB, AP, CC, NJC, LB, GB, RG, GF, DG, CF, MS, ES, JC, AL, RB, MLW, KN, CN, IRAM, GYRH, DMAM, JG, CMM, JA, TDG, IGM, AJT, PP, EDH, EMW, AB, EJ, MCT, PP, CR, SOC, EA, RP, JDS, PA, AK, IR, ER, LP, ER, PStGH, GR, FT, GG, JBR, JCMS, JU, JC, SM, AD, VMVD, MG, JQT, JvdZ, WD, TVL, SFC, ILB, DH, VG, MV, AB, BN, SS, SB, IP, JEN, LEH, MR, MM, BI, GG, SP, WG, MNR, NCF, JDW, MGS, HRM, PR, PH, JSS, SR, AR, AG, ACB, RM, FF, CC, LB, MA, MG, MEC, NS, MB,

KAJ, JEP, WWS, AMK, HR, JCvS, EGPD, HS, YALP, PS, GL, RC, VN, AAP, MF, AP, GM, PS, MK, HHC, CG, FP, AR, VD, FL, DK, LF, SPB, JH, PM and ABS The following authors declare: CVB and MC are inventors on patent applications for GRN and C9orf72. PRS receives speaker fees from Janssen pharmaceutical; RR receives research support from the NIH (R01 NS080882, R01 NS065782, R01 AG026251, R01 NS076471, and P50 AG16574), the ALS Therapy Alliance, and the Consortium for Frontotemporal Degeneration Research, honoraria for lectures or educational activities not funded by industry; RR serves on the medical advisory board of the Association for Frontotemporal Degeneration, on the board of directors of the International Society for Frontotemporal Dementia and holds a patent on methods to screen for the hexanucleotide repeat expansion in the C9ORF72 gene. DWD serves on the editorial boards of the American Journal of Pathology, Journal of Neuropathology and Experimental Neurology, Brain Pathology, Neurobiology of Aging, Journal of Neurology, Neurosurgery, and Psychiatry, Annals of Neurology, and Neuropathology; DWD is supported by NIH grants (P50 AG16574, P50 NS72187, P01 AG03949), the Mangurian Foundation, CurePSP, and the Robert E. Jacoby Professorship for Alzheimer’s Research. NRGR is on the Scientific Advisory Board for Codman, TauRzx multicenter study, Consultation for CYTOX. RCP chairs a Data Monitoring Committee for Pfizer, Inc. and Janssen Alzheimer Immunotherapy, and is a consultant for GE Healthcare and Elan Pharmaceuticals. RCP receives royalties from Oxford University Press for Mild Cognitive Impairment. DK serves as Deputy Editor for Neurology; DK served on a Data Safety Monitoring Board for Lilly Pharmaceuticals, as a consultant to TauRx, was an investigator in clinical trials sponsored by Baxter, Elan Pharmaceuticals, and Forest Pharmaceuticals in the past 2 years and receives research support from the NIH. BFB has served as an investigator for clinical trials sponsored by Cephalon, Inc., Allon Pharmaceuticals and GE Healthcare; BFB receives royalties from the publication of a book entitled Behavioral Neurology Of Dementia (Cambridge Medicine, 2009); BFB has received honoraria from the American Academy of Neurology; BFB serves on the Scientific Advisory Board of the Tau Consortium; BFB receives research support from the National Institute on Aging (P50 AG016574, U01 AG006786, RO1 AG032306, RO1 AG041797) and the Mangurian Foundation. BLM is on the Board Membership of The Larry L. Hillblom Foundation, The John Douglas French Foundation, The Tau Consortium, Sagol School of Neuroscience Tel Aviv University; BLM holds consultancy for Tau Rx, LTD – Chair, Scientific Advisory Board bvFTD Trial Allon Therapeutics – Steering Committee AL-108-231 Study, Bristol-Myers Squibb-Advisory Board, Progressive Supranuclear Palsy (PSP), Neurology Scientific Advisory Board Meeting Siemens Molecular Imaging, Eli Lilly US Alzheimer’s Disease Advisory Board and obtains royalties from Cambridge University Press Guilford Publications, Inc. Neurocase.

Acknowledgements Intramural funding from the National Institute of Neurological Disorders and Stroke (NINDS) and National Institute on Aging (NIA), the Wellcome/MRC Centre on Parkinson’s disease, Alzheimer’s Research UK (ARUK, Grant ARUK-PG2012-18) and by the office of the Dean of the School of Medicine, Department of Internal Medicine, at Texas Tech University Health Sciences Center. We thank Mike Hubank and Kerra Pearce at the Genomic core facility at the Institute of Child Health (ICH), University College of London (UCL), for assisting RF in performing Illumina genotyping experiments

(FTD-GWAS genotyping). This study utilized the high-performance computational capabilities of the Biowulf Linux cluster at the National Institutes of Health, Bethesda, Md. (http://biowulf.nih.gov). North American Brain Expression Consortium (NABEC) - The work performed by the North American Brain Expression Consortium (NABEC) was supported in part by the Intramural Research Program of the National Institute on Aging, National Institutes of Health, part of the US Department of Health and Human Services; project number ZIA AG000932-04. In addition this work was supported by a Research Grant from the Department of Defense, W81XWH-09-2-0128. UK Brain Expression Consortium (UKBEC) - This work performed by the UK Brain Expression Consortium (UKBEC) was supported by the MRC through the MRC Sudden Death Brain Bank (C.S.), by a Project Grant (G0901254 to J.H. and M.W.) and by a Fellowship award (G0802462 to M.R.). D.T. was supported by the King Faisal Specialist Hospital and Research Centre, Saudi Arabia. Computing facilities used at King's College London were supported by the National Institute for Health Research (NIHR) Biomedical Research Centre based at Guy's and St Thomas' NHS Foundation Trust and King's College London. We would like to thank AROS Applied Biotechnology AS company laboratories and Affymetrix for their valuable input. JBJK was supported by the National Health and Medical Resarch Council (NHMRC) Australia, Project Grants 510217 and 1005769; CDS was supported by NHMRC Project Grants 630428 and 1005769; PRS was supported by NHMRC Project Grants 510217 and 1005769 and acknowledges that DNA samples were prepared by Genetic Repositories Australia, supported by NHMRC Enabling Grant 401184; GMH was supported by NHMRC Research Fellowship 630434, Project Grant 1029538, Program Grant 1037746; JRH was supported by the Australian Research Council Federation Fellowship, NHMRC Project Grant 1029538, NHMRC Program Grant 1037746; OP was supported by NHMRC Career Development Fellowship 1022684, Project Grant 1003139. IH, AR and MB acknowledge the patients and controls who participated in this project and the Trinitat Port-Carbó and her family who are supporting Fundació ACE research programs. CC was supported by Grant P30-NS069329-01 and acknowledges that the recruitment and clinical characterization of research participants at Washington University were supported by NIH P50 AG05681, P01 AG03991, and P01 AG026276. LB and GB were supported by the Ricerca Corrente, Italian Ministry of Health; RG was supported by Fondazione CARIPLO 2009-2633, Ricerca Corrente, Italian Ministry of Health; GF was supported by Fondazione CARIPLO 2009-2633. ES was supported by the Italian Ministry of Health; CF was supported by Fondazione Cariplo; MS was supported from the Italian Ministry of Health (Ricerca Corrente) MLW was supported by Government funding of clinical research within NHS Sweden (ALF); KN was supported by Thure Carlsson Foundation; CN was supported by Swedish Alzheimer Fund. IRAM and GYRH were supported by CIHR (grant 74580) PARF (grant C06-01). JG was supported by the NINDS intramural research funds for FTD research. CMM was supported by Medical Research Council UK, Brains for Dementia Research, Alzheimer's Society, Alzheimer's Research UK, National Institutes for Health Research, Department of Health, Yvonne Mairy Bequest and acknowledges that tissue made available for this study was provided by the Newcastle Brain Tissue Resource, which was funded in part by grants G0400074 and G1100540 from the UK MRC, the Alzheimer’s Research Trust and Alzheimer’s Society through the Brains for Dementia Research Initiative and an NIHR Biomedical Research Centre Grant in Ageing and Health, and NIHR Biomedical Research Unit in Lewy Body Disorders. CMM was supported by the UK Department of Health and Medical Research Council and the Research was supported by the National Institute for Health Research Newcastle Biomedical Research Centre based at

Newcastle Hospitals Foundation Trust and Newcastle University and acknowledges that the views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health; JA was supported by MRC, Dunhill Medical Trust, Alzheimer's Research UK; TDG was supported by Wellcome Trust Senior Clinical Fellow; IGM was supported by NIHR Biomedical Research Centre and Unit on Ageing Grants and acknowledges the National Institute for Health Research Newcastle Biomedical Research Centre based at Newcastle Hospitals Foundation Trust and Newcastle University. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health; AJT was supported by Medical Research Council, Alzheimer's Society, Alzheimer's Research UK, National Institutes for Health Research. EJ was supported by NIHR, Newcastle Biomedical Research Centre. PP, CR, SOC and EA were supported partially by FIMA (Foundation for Applied Medical Research); PP acknowledges Manuel Seijo-Martínez (Department of Neurology, Hospital do Salnés, Pontevedra, Spain), Ramon Rene, Jordi Gascon and Jaume Campdelacreu (Department of Neurology, Hospital de Bellvitge, Barcelona, Spain) for providing FTD DNA samples. RP, JDS, PA and AK were supported by German Federal Ministry of Education and Research (BMBF; grant number FKZ 01GI1007A – German FTLD consortium). IR was supported by Ministero dell'Istruzione, dell'Università e della Ricerca (MIUR) of Italy. PStGH was supported by the Canadian Institutes of Health Research, Wellcome Trust, Ontario Research Fund. FT was supported by the Italian Ministry of Health (ricerca corrente) and MIUR grant RBAP11FRE9; GR and GG were supported by the Italian Ministry of Health (ricerca corrente). JBR was supported by Camrbidge NIHR Biomedical Research Centre and Wellcome Trust (088324). JU, JC, SM were supported by the MRC Prion Unit core funding and acknowledge MRC UK, UCLH Biomedical Research Centre, Queen Square Dementia BRU; SM acknowledges the work of John Beck, Tracy Campbell, Gary Adamson, Ron Druyeh, Jessica Lowe, Mark Poulter. AD acknowledges the work of Benedikt Bader and of Manuela Neumann, Sigrun Roeber, Thomas Arzberger and Hans Kretzschmar. VMVD and JQT were supported by Grants AG032953, AG017586 and AG010124; MG was supported by Grants AG032953, AG017586, AG010124 and NS044266; VMVD acknowledges EunRan Suh, PhD for assistance with sample handling and Elisabeth McCarty-Wood for help in selection of cases; JQT acknowledges Terry Schuck, John Robinson and Kevin Raible for assistance with neuropathological evaluation of cases. CVB and the Antwerp site were in part funded by the MetLife Foundation Award for Medical Research (to CVB), the Belgian Science Policy Office Interuniversity Attraction Poles program; the Foundation for Alzheimer Research (SAO-FRA); the Medical Foundation Queen Elisabeth; the Flemish Government Methusalem Excellence award (to CVB.); the Research Foundation Flanders (FWO) and the University of Antwerp Research Fund. JvdZ holds a postdoctoral fellowship of the FWO. CVB and the Antwerp site authors acknowledge the neurologists S. Engelborghs, PP De Deyn, A Sieben, Rik Vandenberghe and the neuropathologist JJ Martin for the clinical and pathological diagnoses. Isabelle Leber and Alexis Brice were supported by the program “Investissements d’avenir” ANR-10- IAIHU-06 and acknowledges the contribution of The French research network on FTLD/FTLD-ALS for the contribution in samples collection. BN, SS, SB and IP were supported by Prin 2010-prot.2010PWNJXK; Cassa di Rispario di Firenze e Cassa di Risparmio di Pistoia e Pescia. JEN was supported by the Novo Nordisk Foundation, Denmark. MR was supported by the German National Genome Network (NGFN); German Ministry for Education and Research Grant Number 01GS0465. JDR, MNR, NCF and JDW were supported by an MRC programme grant, the NIHR Queen Square Dementia Biomedical Research Unit and the Leonard Wolfson Experimental Neurology Centre.

MGS was supported by MRC grant n G0301152, Cambridge Biomedical Research Centre and acknowledges Mrs K Westmore for extracting DNA. HM was supported by the Motor Neuron Disease Association (Grant 6057). RR was supported by P50 AG016574, R01 NS080882, R01 NS065782, P50 NS72187 and the Consortium for Frontotemporal Dementia; DWD was supported by P50NS072187, P50AG016574, State of Florida Alzheimer Disease Initiative, & CurePSP, Inc.; NRGR, JEP, RCP, DK, BFB were supported by P50 AG016574; KAJ was supported by R01 AG037491; WWS was supported by NIH AG023501, AG019724, Consortium for Frontotemporal Dementia Research; BLM was supported by P50AG023501, P01AG019724, Consortium for FTD Research; HR was supported by AG032306. JCvS was supported by Stichting Dioraphte Foundation (11 02 03 00), Nuts Ohra Foundation (0801-69), Hersenstichting Nederland (BG 2010-02) and Alzheimer Nederland. CG and HHC acknowledge families, patients, clinicians including Dr Inger Nennesmo and Dr Vesna Jelic, Professor Laura Fratiglioni for control samples and Jenny Björkström, Håkan Thonberg, Charlotte Forsell, Anna-Karin Lindström and Lena Lilius for sample handling. CG was supported by Swedish Brain Power (SBP), the Strategic Research Programme in Neuroscience at Karolinska Institutet (StratNeuro), the regional agreement on medical training and clinical research (ALF) between Stockholm County Council and Karolinska Institutet, Swedish Alzheimer Foundation, Swedish Research Council, Karolinska Institutet PhD-student funding, King Gustaf V and Queen Victoria’s Free Mason Foundation. FP, AR, VD and FL acknowledge Labex DISTALZ. RF acknowledges the help and support of Mrs. June Howard at the Texas Tech University Health Sciences Center Office of Sponsored Programs for tremendous help in managing Material Transfer Agreement at TTUHSC. UKBEC and NABEC members: Michael E Weale, Department of Medical and Molecular Genetics, King¹s College London, 8th Floor, Tower Wing, Guy¹s Hospital, London SE1 9RT, UK; Mina Ryten, Reta Lila Weston Institute and Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK; Adaikalavan Ramasamy, Department of Medical and Molecular Genetics, King¹s College London, 8th Floor, Tower Wing, Guy¹s Hospital, London SE1 9RT, UK, Reta Lila Weston Institute and Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK; Daniah Trabzuni, Reta Lila Weston Institute and Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK, Department of Genetics, King Faisal Specialist Hospital and Research Centre, PO Box 3354, Riyadh 11211, Saudi Arabia; Colin Smith, Department of Neuropathology, MRC Sudden Death Brain Bank Project, University of Edinburgh, Wilkie Building, Teviot Place, Edinburgh EH8 9AG; Robert Walker, Department of Neuropathology, MRC Sudden Death Brain Bank Project, University of Edinburgh, Wilkie Building, Teviot Place, Edinburgh EH8 9AG. Mark R Cookson, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA; J. Raphael Gibbs, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA, Reta Lila Weston Institute and Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK; Allissa Dillman, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA, Department of Neuroscience, Karolinska Institutet, 171 77 Stockholm, Sweden; Alan B Zonderman, Research Resources Branch, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA; Sampath Arepalli, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of

Health, Bethesda, MD, USA; Luigi Ferrucci, Clinical Research Branch, National Institute on Aging, Baltimore, MD, USA; Robert Johnson, NICHD Brain and Tissue Bank for Developmental Disorders, University of Maryland Medical School, Baltimore, Maryland 21201, USA; Dan L Longo, Lymphocyte Cell Biology Unit, Laboratory of Immunology, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA; Richard O'Brien, Brain Resource Center, Johns Hopkins University, Baltimore, MD, USA; Bryan Traynor, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA; Juan Troncoso, Brain Resource Center, Johns Hopkins University, Baltimore, MD, USA; Marcel van der Brug, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA, ITGR Biomarker Discovery Group, Genentech, South San Francisco, CA, USA; Ronald H Zielke, NICHD Brain and Tissue Bank for Developmental Disorders, University of Maryland Medical School, Baltimore, Maryland 21201, USA.

French research network on FTLD/FTLD-ALS members: Sophie Auriacombe (CHU Pellegrin, Bordeaux), Alexis Brice (Hôpital de la Salpêtrière, Paris), Agnès Camuzat (CR-ICM, Paris), Frédéric Blanc (Hôpitaux Civils, Strasbourg), Philippe Couratier (CHU Limoges), Mira Didic (CHU La Timone, Marseille), Bruno Dubois (Hôpital de la Salpêtrière, Paris), Charles Duyckaerts (Hôpital de la Salpêtrière, Paris), Marie-Odile Habert (Hôpital de la Salpêtrière, Paris), Véronique Golﬁer (CHU Rennes), Eric Guedj (CHU Marseille), Didier Hannequin (CHU Charles Nicolle, Rouen), Lucette Lacomblez (Hôpital de la Salpêtrière, Paris), Isabelle Le Ber (Hôpital de la Salpêtrière, Paris), Richard Levy (CHU St Antoine, Paris), Vincent Meininger (Hôpital de la Salpêtrière, Paris), Bernard- François Michel (CH SainteMarguerite, Marseille), Florence Pasquier (CHU Roger Salengro, Lille), Catherine Thomas-Anterion (CHU Bellevue, Saint-Etienne), Michèle Puel (CHU Rangueil, Toulouse), François Salachas (Hôpital de la Salpêtrière, Paris), François Sellal (CH Colmar), Martine Vercelletto (CHU Laennec, Nantes), and Patrice Verpillat (Hôpital de la Salpêtrière, Paris). The Belgian Neurology consortium, abbreviated as BELNEU consortium and The European Early-Onset Dementia consortium, abbreviated EU EOD consortium both coordinated by Christine Van Broeckhoven. Peter P. De Deyn, Sebastiaan Engelborghs, Dirk Nuytten (Hospital Network Antwerp, Antwerp, Belgium); Patrick Cras,Peter De Jonghe, Katrien Smets, Jonathan Baets (Antwerp University Hospital, Edegem, Belgium); Jean-Jacques Martin (Institute Born-Bunge, University of Antwerp, Antwerp, Belgium); Rik Vandenberghe, Mathieu Vandenbulcke, Wim Robberecht, Philip Van Damme (University Hospitals Leuven Gasthuisberg, Leuven, Belgium); Jan De Bleecker, Patrick Santens, Anne Sieben, Bart Dermaut (University Hospital Ghent, Ghent, Belgium); Adrian Ivanoiu (Saint-Luc University Hospital, Brussels, Belgium); Olivier Deryck, Bruno Bergmans (AZ Sint-Jan Brugge, Bruges, Belgium); Alex Michotte, Jan Versijpt (University Hospital Brussels, Brussels, Belgium); Christiana Willems (Jessa Hospital, Hasselt, Belgium); Eric Salmon (University of Liège, Liège, Belgium). Wiesje Van der Flier (VU University Medical Centre, Amsterdam, The Netherlands); Cornelia Van Duijn (Erasmus University Rotterdam, Rotterdam, The Netherlands); Peter P. De Deyn (University Medical Center Groningen, Groningen, The Netherlands); Alexis Brice (Inserm, UMR_S975 and Salpêtrière Hospital, Paris, France); Bruno Dubois (Salpêtrière Hospital, Pierre & Marie Curie University, Paris, France); Florence Pasquier (Université Lille Nord de France, Lille, France); Dominique Campion (University of Rouen, France); Matthias

Riemenschneider (Saarland University; University Hospital, Homburg/Saar, Germany); Markus Otto (Universitätsklinikum Ulm, Ulm, Germany); Adrian Danek (Ludwig-Maximilians-Universität and DZNE, Munich, Germany); Panos Alexopoulos (Technische Universität Münich, Münich, Germany); Matthis Synofzik (Hertie Institute for Clinical Brain Research and DZNE, Tübingen, Germany); Manuela Neumann (University of Tübingen,Tübingen, Germany); Alfredo Ramirez, Michael Heneka, Frank Jessen (University of Bonn and DZNE, Bonn, Germany); Rachel Sanchez-Valle (Alzheimer's disease and other cognitive disorders unit and Hospital Clínic, IDIBAPS, Barcelona, Spain); Jordi Clarimón (Universitat Autònoma de Barcelona, Barcelona and (CIBERNED), Madrid, Spain.); Ellen Gelpi (Biobanc-Hospital Clinic-Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, Spain); Merce Boada (Memory Clinic of Fundació ACE, Barcelona, Spain); Pau Pastor (Universidad de Navarra, and University of Navarra School of Medicine, Pamplona, and Instituto de Salud Carlos III, Madrid, Spain); Alexandre de Mendonça (University of Lisbon, Lisbon, Portugal); Isabel Santana (Centro Hospitalar Universitário de Coimbra, Coimbra and University of Coimbra, Coimbra, Portugal); Alessandro Padovani (University of Brescia, Brescia, Italy); Sandro Sorbi (NEUROFARBA, University of Florence, Florence, Italy); Giovanni Frisoni (LENITEM, IRCCS Fatebenefratelli, Brescia, Italy); Luisa Benussi (NeuroBioGen Lab-Memory Clinic, IRCCS Fatebenefratelli, Brescia, Italy); Maura Gallo (Regional Neurogenetic Centre, Lamezia Terme, Italy); Gian Maria Fabrizi (University of Verona, Verona, Italy); Gabor Kovacs (Medical University of Vienna, Vienna, Austria); Radek Matej (Thomayer Hospital and Charles University, Prague, Czech Republic); Maria Judit Molnar (Semmelweis University, Budapest, Hungary); Stayko Sarafov, Ivailo Tournev, Shima Mehrabian (Medical University Sofia, Sofia, Bulgaria); Jørgen Erik Nielsen, Gunhild Waldemar (Copenhagen University Hospital, Copenhagen, Denmark); Jørgen Erik Nielsen (The Panum Institute, University of Copenhagen, Copenhagen, Denmark); Michael Bjørn Petersen, Karsten Vestergård (Aalborg Hospital, Aalborg, Denmark); Caroline Graff (Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden); Mikko Hiltunen (University of Eastern Finland and Institute of Clinical Medicine, Kuopio, Finland ); Magda Tsolaki (Aristotle University of Thessaloniki, Thessaloniki, Greece.); Sermin Genc (University of Dokuz Eylul, Izmir, Turkey).

References 1 Neary D, Snowden JS, Gustafson L et al. Frontotemporal lobar degeneration: a consensus on clinical diagnostic criteria. Neurology 1998; 51: 1546-54 2 Rabinovici GD, Miller BL. Frontotemporal lobar degeneration: epidemiology, pathophysiology, diagnosis and management. CNS Drugs 2010; 24: 375-98 3 Rohrer JD, Warren JD. Phenotypic signatures of genetic frontotemporal dementia. Curr Opin Neurol 2011; 24: 542-49 4 Rascovsky K, Hodges JR, Knopman D et al. Sensitivity of revised diagnostic criteria for the behavioural variant of frontotemporal dementia. Brain 2011; 134: 2456-77 5 Gorno-Tempini ML, Hillis AE, Weintraub S et al. Classification of primary progressive aphasia and its variants. Neurology 2011; 76: 1006-14 6 Mackenzie IR, Neumann M, Baborie A et al. A harmonized classification system for FTLD-TDP pathology. Acta Neuropathol 2011; 122: 111-3 7 Halliday G, Bigio EH, Cairns NJ, Neumann M, Mackenzie IR, Mann DM. Mechanisms of disease in frontotemporal lobar degeneration: gain of function versus loss of function effects. Acta Neuropathol 2012; 124: 373-82 8 Hutton M, Lendon CL, Rizzu P et al. Association of missense and 5'-splice-site mutations in tau with the inherited dementia FTDP-17. Nature 1998; 393: 702-5 9 Baker M, Mackenzie IR, Pickering-Brown SM et al. Mutations in progranulin cause tau- negative frontotemporal dementia linked to chromosome 17. Nature 2006; 442: 916-9 10 Cruts M, Gijselinck I, van der Zee J et al. Null mutations in progranulin cause ubiquitin- positive frontotemporal dementia linked to chromosome 17q21. Nature 2006; 442: 920-4 11 DeJesus-Hernandez M, Mackenzie IR, Boeve BF et al. Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS. Neuron 2011; 72: 245-56 12 Renton AE, Majounie E, Waite A et al. A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD. Neuron 2011; 72: 257-68 13 Ferrari R, Thumma A, Momeni P. Molecular Genetics of Frontotemporal Dementia. In: eLS. John Wiley & Sons, Ltd: Chichester. 2013 DOI: 10.1002/9780470015902.a0024457 14 van der Zee J, Gijselinck I, Dillen L et al. A Pan-European Study of the C9orf72 Repeat Associated with FTLD: Geographic Prevalence, Genomic Instability, and Intermediate Repeats. Hum mutat 2013; 34: 363-73 15 Rohrer JD, Rosen HJ. Neuroimaging in frontotemporal dementia. Int Rev Psychiatry 2013; 25: 221-9 16 Ling SC, Polymenidou M, Cleveland DW. Converging Mechanisms in ALS and FTD: Disrupted RNA and Protein Homeostasis. Neuron 2013; 79: 416-38 17 Van Deerlin VM, Sleiman PM, Martinez-Lage M et al. Common variants at 7p21 are associated with frontotemporal lobar degeneration with TDP-43 inclusions. Nat Genet 2010; 42: 234-9

18 Strong MJ, Grace GM, Freedman M et al. Consensus criteria for the diagnosis of frontotemporal cognitive and behavioural syndromes in amyotrophic lateral sclerosis. Amyotroph Lateral Scler 2009; 10: 131-46 19 International Parkinson Disease Genomics Consortium, Nalls MA, Plagnol V et al. Imputation of sequence variants for identification of genetic risks for Parkinson's disease: a meta- analysis of genome-wide association studies. Lancet 2011; 377: 641-9 20 1000 Genomes Project Consortium, Abecasis GR, Auton A et al. An integrated map of genetic variation from 1,092 human genomes. Nature 2012; 491: 56–65 21 International HapMap 3 Consortium, Altshuler DM, Gibbs RA et al. Integrating common and rare genetic variation in diverse human populations. Nature 2010; 467: 52–58 22 Price AL, Patterson NJ, Plenge RM, Weinblatt ME, Shadick NA, Reich D. Principal components analysis corrects for stratification in genome-wide association studies. Nature Gen 2006; 38: 904-9 23 Grove ML, Yu B, Cochran BJ et al. Best Practices and Joint Calling of the HumanExome BeadChip: The CHARGE Consortium. PLoS One 2013; 8: e68095 24 Millar T, Walker R, Arango JC et al. Tissue and organ donation for research in forensic pathology: the MRC Sudden Death Brainand Tissue Bank. J Pathol 2007; 213: 369-75 25 Beach TG, Sue LI, Walker DG et al. The Sun Health Research Institute Brain Donation Program: description and experience, 1987-2007. Cell Tissue Bank 2008; 9: 229-45 26 Hawrylycz MJ, Lein ES, Guillozet-Bongaarts AL et al. An anatomically comprehensive atlas of the adult human brain transcriptome. Nature 2012; 489: 391-9 27 Kang HJ, Kawasawa YI, Cheng F et al. Spatio-temporal transcriptome of the human brain. Nature 2011; 478: 483-9 28 Roth RB, Hevezi P, Lee J et al. Gene expression analyses reveal molecular relationships among 20 regions of the human CNS. Neurogenetics 2006; 7: 67-80 29 Trabzuni D, Ryten M, Walker R et al. Quality control parameters on a large dataset of regionally dissected human control brains for whole genome expression studies. J Neurochem 2011; 119: 275-82 30 Irizarry RA, Hobbs B, Collin F et al. Exploration, normalization, and summaries of high density oligonucleotide array probe level data. Biostatistics 2003; 4: 249-64 31 Ramasamy A, Trabzuni D, Gibbs JR et al. Resolving the polymorphism-in-probe problem is critical for correct interpretation of expression QTL studies. Nucleic Acids Res 2013; 41: e88 32 International Parkinson's Disease Genomics Consortium (IPDGC); Wellcome Trust Case Control Consortium 2 (WTCCC2). A two-stage meta-analysis identifies several new loci for Parkinson's disease. PLoS Genet 2011; 7: e1002142 33 Li Y, Willer C, Sanna S, Abecasis G. Genotype imputation. Annu Rev Genomics Hum Genet 2009; 10: 387-406 34 Li Y, Willer CJ, Ding J, Scheet P, Abecasis GR. MaCH: using sequence and genotype data to estimate haplotypes and unobserved genotypes. Genet Epidemiol 2010; 34: 816-34 35 Gibbs JR, van der Brug MP, Hernandez DG et al. Abundant quantitative trait loci exist for DNA methylation and gene expression in human brain. PLoS Genet 2010; 6: e1000952

36 Barbosa-Morais NL, Dunning MJ, Samarajiwa SA et al. A re-annotation pipeline for Illumina BeadArrays: improving the interpretation of gene expression data. Nucleic Acids Res 2010; 38: e17 37 Shabalin AA. Matrix eQTL: Ultra fast eQTL analysis via large matrix operations. Bioinformatics 2012; 28: 1353-8 38 Zeller T, Wild P, Szymczak S et al. Genetics and beyond–the transcriptome of human monocytes and disease susceptibility. PLoS One 2010; 5: e10693 39 van Es MA, Veldink JH, Saris CG et al. Genome-wide association study identifies 19p13.3 (UNC13A) and 9p21.2 as susceptibility loci for sporadic amyotrophic lateral sclerosis. Nat Genet 2009; 41: 1083-7 40 Höglinger GU, Melhem NM, Dickson DW et al. Identification of common variants influencing risk of the tauopathy progressive supranuclear palsy. Nat Genet 2011; 43: 699-705 41 Seshadri S, Fitzpatrick AL, Ikram MA et al. Genome-wide analysis of genetic loci associated with Alzheimer disease. JAMA 2010; 303: 1832-40 42 van der Zee J, Sleegers K, Van Broeckhoven C. Invited article: the Alzheimer disease- frontotemporal lobar degeneration spectrum. Neurology 2008; 71: 1191-7 43 Baranzini SE, Wang J, Gibson RA et al. Genome wide association analysis of susceptibility and clinical phenotype in multiple sclerosis. Hum Mol Genet 2009; 18: 767-78 44 International Multiple Sclerosis Genetics Consortium, Hafler DA, Compston A et al. Risk alleles for multiple sclerosis identified by a genomewide study. N Engl J Med 2007; 357: 851- 62 45 Mero IL, Gustavsen MW, Sæther HS et al. Oligoclonal band status in Scandinavian multiple sclerosis patients is associated with specific genetic risk alleles. PLoS One 2013; 8: e58352 46 Hamza TH, Zabetian CP, Tenesa A et al. Common genetic variation in the HLA region is associated with late-onset sporadic Parkinson's disease. Nat Genet 2010; 42: 781-5 47 Lambert JC, Ibrahim-Verbaas CA, Harold D et al. Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer's disease. Nat Genet 2013; 45:1452-1458 48 Jäger D, Stockert E, Jäger E et al. Serological cloning of a melanocyte rab guanosine 5-prime- triphosphate-binding protein and a chromosome condensation protein from a melanoma complementary DNA library. Cancer Res 2000; 60: 3584-359 49 Bultema JJ, Ambrosio AL, Burek CL, Di Pietro SM. BLOC-2, AP-3, and AP-1 proteins function in concert with Rab38 and Rab32 proteins to mediate protein trafficking to lysosome-related organelles. J Biol Chem 2012; 287: 19550-63 50 Seto S, Tsujimura K, Koide Y. Rab GTPAses regulating phagosome maturation are differentially recruited to mycobacterial phagosomes. Traffic 2011; 12: 407-20 51 Hu F, Padukkavidana T, Vægter CB et al. Sortilin-mediated endocytosis determines levels of the frontotemporal dementia protein, progranulin. Neuron 2010; 68: 654-67 52 Brady OA, Zheng Y, Murphy K, Huang M, Hu F. The frontotemporal lobar degeneration risk factor, TMEM106B, regulates lysosomal morphology and function. Hum Mol Genet 2013; 22: 685-95 53 Westbroek W, Gustafson AM, Sidransky E. Exploring the link between glucocerebrosidase mutations and parkinsonism. Trends Mol Med 2011; 17: 485-93

54 Hardy J1, Rogaeva E Motor neuron disease and frontotemporal dementia: sometimes related, sometimes not. Exp Neurol 2013 pii: S0014-4886(13)00330-0 55 Amor S, Woodroof N. Review series on immune responses in neurodegenerative diseases: innate and adaptive immune responses in neurodegeneration and repair. Immunology 2013; doi: 10.1111/imm.12134 56 Träger U, Tabrizi SJ. Peripheral inflammation in neurodegeneration. J Mol Med 2013; 91: 673–81

*Manuscript with revisions highlighted

Frontotemporal dementia and its subtypes: a genome wide association study

Findings We identified novel associations exceeding the genome wide significance threshold (p- value<5x10-8) that encompassed the HLA locus at 6p21·3 in the entire cohort. We also identified a potential novel locus at 11q14, encompassing RAB38/CTSC for the bvFTD subtype. Analysis of expression and methylation quantitative trait loci (e/mQTL) data suggested that these loci might affect expression and methylation in-cis.

Funding Intramural funding from the National Institute of Neurological Disorders and Stroke (NINDS) and National Institute on Aging (NIA), the Wellcome/MRC Centre on Parkinson’s disease, Alzheimer’s Research UK (ARUK), and Texas Tech University Health Sciences Center (TTUHSC) office of the Dean.

Materials and Methods

DNA Quality Control For each sample, a total amount of 2μg of DNA extracted either from blood or brain at each collaborative site was collected (whole genome amplified DNA samples were excluded).

Samples were securely stored in -20°C freezers. Each sample was first screened for integrity by means of gel electrophoresis on 1% agarose gel and purity, as well as concentration were analyzed by

8 spectrophotometric (Nanodrop, Wilmington, DE, USA) or fluorometric (Qubit, Life Technologies, Grand Island, NY, USA) quantification. The same procedure was implemented at UCL, NIH and TTUHSC.

Statistical methods and quality control

9 in R was used to match cases to controls. Each subtype (bvFTD, SD, PNFA and FTD-MND) was treated as separate groups in which the two most genetically similar unique controls per case were selected based on eigenvectors 1 and 2. This was carried out to compensate for a lack of precisely matched controls at recruitment / study design. In this aspect, matched controls were unique per case and non- redundant across subtype datasets. Thus, cases and controls were matched for each subtype (bvFTD, SD, PNFA and FTD-MND) based on similarity of the first two eigenvectors from PCA and did not overlap across subtypes. Logistic regression was used based on imputed dosages to assess the association between each SNP and FTD or any of the FTD subtypes, adjusting for eigenvectors 1 and 2 from PCA as covariates. Eigenvectors were generated separately for each subtype, as in the overall sample pool, parameter estimates for the first 2 were associated with case status at p-values < 0·05. Fixed effects meta-analyses were performed to combine results across subtypes and quantify heterogeneity across subtypes. Genomic inflation was minimal across subtypes and in the meta-analysis across subtypes (lambda <1·05), therefore we did not use genomic control (see Supplementary Figure SF1, webappendix pp 4, for quantile-quantile plots and lambda values per discovery phase analysis). SNPs were imputed to August 2010 release of the 1000 genome haplotypes using default settings of minimac [http://genome.sph.umich.edu/wiki/Minimac] and were excluded if their MAF was <0·01 or imputation quality (Rsq) was <0·30 across all samples, leaving 6026385 SNPs for analyses.

Expression and methylation quantitative trait loci (QTL)

UK Brain Expression Consortium (UKBEC)

North American Brain Expression Consortium (NABEC)

Discussion Frontotemporal dementia is characterized by a broad range of clinical manifestations, differential pathological signatures and considerable genetic variability implying to complex disease mechanisms.15 In the search for novel disease risk loci associated with FTD we have performed an extensive GWAS on a large cohort of mainly clinically diagnosed FTD samples of European ancestry. It needs to be acknowledged that a number of limitations may apply to this study. Given phenotype heterogeneity in the clinical presentation of FTD and considering that it is a rare neurodegenerative disorder (low prevalence),2 testing the hypothesis “common variant – common disease” for diseases of this kind is challenging and clearly benefits from large sample sizes. In addition, there was an overall need during this work for robust statistical adjustments to correct for potential confounding factors due to population stratification, cases and controls matching and for differences in arrays used to generate genotyping data during the discovery phase. Nevertheless, In addition, based on the nature of this study, our study may indicate association with specific loci without necessarily implying causality; low heritability due to common variability may also apply. However, importantly, the QQ plots and associated lambda values (Supplementary Figure SF1, webappendix pp 4) conformed to GWAS standards, supporting confidence in the final results, eventually.

Our current study included totally more than 3,500 cases and, in this respect, it is the largest GWAS for FTD to date. We have identified two novel potential loci for FTD: 11q14, encompassing RAB38/CTSC was suggestive for the bvFTD subtype, and 6p21·3, encompassing the HLA locus was significant for the entire cohort.

Panel: Research in context

16 was only one directly relevant study that investigated a pathologically defined subtype of FTD (FTLD- TDP).17 The other studies concerned related diseases such as ALS39, AD41,47, PSP/CBD40 , MS43-45 and PD.19,46 In our current study, we analyzed a total of 3,526 (after QC) FTD samples obtained from more than 40 international research groups and we carefully selected those samples eligible for genotyping and those to be included in the analyses to generate our association data. Samples and genotyping data were rigorously filtered through high standard QC steps to assess diagnosis, DNA quality and genotyping output data quality (see Material and Methods section). In this association study all genotyping data have been generated and analyzed within the consortium.

' RF, DGH, MAN and JDR contributed equally. * ABS, JH and PM joint last authors.

VMVD, MG, JQT, JvdZ, WD, TVL, SFC, ILB, DH, VG, MV, AB, BN, SS, SB, IP, JEN, LEH, MR, MM, BI, GG, SP, WG, MNR, NCF, JDW, MGS, HRM, PR, PH, JSS, SR, AR, AG, ACB, RM, FF, CC, LB, MA, MG, MEC, NS, MB, KAJ, JEP, WWS, AMK, HR, JCvS, EGPD, HS, YALP, PS, GL, RC, VN, AAP, MF, AP, GM, PS, MK, HHC, CG, FP, AR, VD, FL, DK, LF, SPB, JH, PM and ABS The following authors declare: CVB and MC are inventors on patent applications for GRN and C9orf72. PRS receives speaker fees from Janssen pharmaceutical; RR receives research support from the NIH (R01 NS080882, R01 NS065782, R01 AG026251, R01 NS076471, and P50 AG16574), the ALS Therapy Alliance, and the Consortium for Frontotemporal Degeneration Research, honoraria for lectures or educational activities not funded by industry; RR serves on the medical advisory board of the Association for Frontotemporal Degeneration, on the board of directors of the International Society for Frontotemporal Dementia and holds a patent on methods to screen for the hexanucleotide repeat expansion in the C9ORF72 gene. DWD serves on the editorial boards of the American Journal of Pathology, Journal of Neuropathology and Experimental Neurology, Brain Pathology, Neurobiology of Aging, Journal of Neurology, Neurosurgery, and Psychiatry, Annals of Neurology, and Neuropathology; DWD is supported by NIH grants (P50 AG16574, P50 NS72187, P01 AG03949), the Mangurian Foundation, CurePSP, and the Robert E. Jacoby Professorship for Alzheimer’s Research. NRGR is on the Scientific Advisory Board for Codman, TauRzx multicenter study, Consultation for CYTOX. RCP chairs a Data Monitoring Committee for Pfizer, Inc. and Janssen Alzheimer Immunotherapy, and is a consultant for GE Healthcare and Elan Pharmaceuticals. RCP receives royalties from Oxford University Press for Mild Cognitive Impairment. DK serves as Deputy Editor for Neurology; DK served on a Data Safety Monitoring Board for Lilly Pharmaceuticals, as a consultant to TauRx, was an investigator in clinical trials sponsored by Baxter, Elan Pharmaceuticals, and Forest Pharmaceuticals in the past 2 years and receives research support from the NIH. BFB has served as an investigator for clinical trials sponsored by Cephalon, Inc., Allon Pharmaceuticals and GE Healthcare; BFB receives royalties from the publication of a book entitled Behavioral Neurology Of Dementia (Cambridge Medicine, 2009); BFB has received honoraria from the American Academy of Neurology; BFB serves on the Scientific Advisory Board of the Tau Consortium; BFB receives research support from the National Institute on Aging (P50 AG016574, U01 AG006786, RO1 AG032306, RO1 AG041797) and the Mangurian Foundation. BLM is on the Board Membership of The Larry L. Hillblom Foundation, The John Douglas French Foundation, The Tau Consortium, Sagol School of Neuroscience Tel Aviv University; BLM holds consultancy for Tau Rx, LTD – Chair, Scientific Advisory Board bvFTD Trial Allon Therapeutics – Steering Committee AL-108-231 Study, Bristol-Myers Squibb-Advisory Board, Progressive Supranuclear Palsy (PSP), Neurology Scientific Advisory Board Meeting Siemens Molecular Imaging, Eli Lilly US Alzheimer’s Disease Advisory Board and obtains royalties from Cambridge University Press Guilford Publications, Inc. Neurocase.

We thank Mike Hubank and Kerra Pearce at the Genomic core facility at the Institute of Child Health (ICH), University College of London (UCL), for assisting RF in performing Illumina genotyping experiments (FTD-GWAS genotyping). This study utilized the high-performance computational capabilities of the Biowulf Linux cluster at the National Institutes of Health, Bethesda, Md. (http://biowulf.nih.gov). North American Brain Expression Consortium (NABEC) - The work performed by the North American Brain Expression Consortium (NABEC) was supported in part by the Intramural Research Program of the National Institute on Aging, National Institutes of Health, part of the US Department of Health and Human Services; project number ZIA AG000932-04. In addition this work was supported by a Research Grant from the Department of Defense, W81XWH-09-2-0128. UK Brain Expression Consortium (UKBEC) - This work performed by the UK Brain Expression Consortium (UKBEC) was supported by the MRC through the MRC Sudden Death Brain Bank (C.S.), by a Project Grant (G0901254 to J.H. and M.W.) and by a Fellowship award (G0802462 to M.R.). D.T. was supported by the King Faisal Specialist Hospital and Research Centre, Saudi Arabia. Computing facilities used at King's College London were supported by the National Institute for Health Research (NIHR) Biomedical Research Centre based at Guy's and St Thomas' NHS Foundation Trust and King's College London. We would like to thank AROS Applied Biotechnology AS company laboratories and Affymetrix for their valuable input. JBJK was supported by the National Health and Medical Resarch Council (NHMRC) Australia, Project Grants 510217 and 1005769; CDS was supported by NHMRC Project Grants 630428 and 1005769; PRS was supported by NHMRC Project Grants 510217 and 1005769 and acknowledges that DNA samples were prepared by Genetic Repositories Australia, supported by NHMRC Enabling Grant 401184; GMH was supported by NHMRC Research Fellowship 630434, Project Grant 1029538, Program Grant 1037746; JRH was supported by the Australian Research Council Federation Fellowship, NHMRC Project Grant 1029538, NHMRC Program Grant 1037746; OP was supported by NHMRC Career Development Fellowship 1022684, Project Grant 1003139. IH, AR and MB acknowledge the patients and controls who participated in this project and the Trinitat Port-Carbó and her family who are supporting Fundació ACE research programs. CC was supported by Grant P30-NS069329-01 and acknowledges that the recruitment and clinical characterization of research participants at Washington University were supported by NIH P50 AG05681, P01 AG03991, and P01 AG026276. LB and GB were supported by the Ricerca Corrente, Italian Ministry of Health; RG was supported by Fondazione CARIPLO 2009-2633, Ricerca Corrente, Italian Ministry of Health; GF was supported by Fondazione CARIPLO 2009-2633. ES was supported by the Italian Ministry of Health; CF was supported by Fondazione Cariplo; MS was supported from the Italian Ministry of Health (Ricerca Corrente) MLW was supported by Government funding of clinical research within NHS Sweden (ALF); KN was supported by Thure Carlsson Foundation; CN was supported by Swedish Alzheimer Fund. IRAM and GYRH were supported by CIHR (grant 74580) PARF (grant C06-01). JG was supported by the NINDS intramural research funds for FTD research. CMM was supported by Medical Research Council UK, Brains for Dementia Research, Alzheimer's Society, Alzheimer's Research UK, National Institutes for Health Research, Department of Health, Yvonne Mairy Bequest and acknowledges that tissue made available for this study was provided by the Newcastle Brain Tissue Resource, which was funded in part by grants G0400074 and G1100540 from the UK MRC, the Alzheimer’s Research Trust and Alzheimer’s Society through the Brains for Dementia Research Initiative and an NIHR Biomedical Research Centre Grant in Ageing and Health, and NIHR Biomedical Research Unit in Lewy Body Disorders. CMM was

19 supported by the UK Department of Health and Medical Research Council and the Research was supported by the National Institute for Health Research Newcastle Biomedical Research Centre based at Newcastle Hospitals Foundation Trust and Newcastle University and acknowledges that the views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health; JA was supported by MRC, Dunhill Medical Trust, Alzheimer's Research UK; TDG was supported by Wellcome Trust Senior Clinical Fellow; IGM was supported by NIHR Biomedical Research Centre and Unit on Ageing Grants and acknowledges the National Institute for Health Research Newcastle Biomedical Research Centre based at Newcastle Hospitals Foundation Trust and Newcastle University. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health; AJT was supported by Medical Research Council, Alzheimer's Society, Alzheimer's Research UK, National Institutes for Health Research. EJ was supported by NIHR, Newcastle Biomedical Research Centre. PP, CR, SOC and EA were supported partially by FIMA (Foundation for Applied Medical Research); PP acknowledges Manuel Seijo-Martínez (Department of Neurology, Hospital do Salnés, Pontevedra, Spain), Ramon Rene, Jordi Gascon and Jaume Campdelacreu (Department of Neurology, Hospital de Bellvitge, Barcelona, Spain) for providing FTD DNA samples. RP, JDS, PA and AK were supported by German Federal Ministry of Education and Research (BMBF; grant number FKZ 01GI1007A – German FTLD consortium). IR was supported by Ministero dell'Istruzione, dell'Università e della Ricerca (MIUR) of Italy. PStGH was supported by the Canadian Institutes of Health Research, Wellcome Trust, Ontario Research Fund. FT was supported by the Italian Ministry of Health (ricerca corrente) and MIUR grant RBAP11FRE9; GR and GG were supported by the Italian Ministry of Health (ricerca corrente). JBR was supported by Camrbidge NIHR Biomedical Research Centre and Wellcome Trust (088324). JU, JC, SM were supported by the MRC Prion Unit core funding and acknowledge MRC UK, UCLH Biomedical Research Centre, Queen Square Dementia BRU; SM acknowledges the work of John Beck, Tracy Campbell, Gary Adamson, Ron Druyeh, Jessica Lowe, Mark Poulter. AD acknowledges the work of Benedikt Bader and of Manuela Neumann, Sigrun Roeber, Thomas Arzberger and Hans Kretzschmar. VMVD and JQT were supported by Grants AG032953, AG017586 and AG010124; MG was supported by Grants AG032953, AG017586, AG010124 and NS044266; VMVD acknowledges EunRan Suh, PhD for assistance with sample handling and Elisabeth McCarty-Wood for help in selection of cases; JQT acknowledges Terry Schuck, John Robinson and Kevin Raible for assistance with neuropathological evaluation of cases. CVB and the Antwerp site were in part funded by the MetLife Foundation Award for Medical Research (to CVB), the Belgian Science Policy Office Interuniversity Attraction Poles program; the Foundation for Alzheimer Research (SAO-FRA); the Medical Foundation Queen Elisabeth; the Flemish Government Methusalem Excellence award (to CVB.); the Research Foundation Flanders (FWO) and the University of Antwerp Research Fund. JvdZ holds a postdoctoral fellowship of the FWO. CVB and the Antwerp site authors acknowledge the neurologists S. Engelborghs, PP De Deyn, A Sieben, Rik Vandenberghe and the neuropathologist JJ Martin for the clinical and pathological diagnoses. Isabelle Leber and Alexis Brice were supported by the program “Investissements d’avenir” ANR-10- IAIHU-06 and acknowledges the contribution of The French research network on FTLD/FTLD-ALS for the contribution in samples collection. BN, SS, SB and IP were supported by Prin 2010-prot.2010PWNJXK; Cassa di Rispario di Firenze e Cassa di Risparmio di Pistoia e Pescia. JEN was supported by the Novo Nordisk Foundation, Denmark. MR was supported by the German National Genome Network (NGFN); German Ministry for Education and Research Grant Number 01GS0465.

JDR, MNR, NCF and JDW were supported by an MRC programme grant, the NIHR Queen Square Dementia Biomedical Research Unit and the Leonard Wolfson Experimental Neurology Centre. MGS was supported by MRC grant n G0301152, Cambridge Biomedical Research Centre and acknowledges Mrs K Westmore for extracting DNA. HM was supported by the Motor Neuron Disease Association (Grant 6057). RR was supported by P50 AG016574, R01 NS080882, R01 NS065782, P50 NS72187 and the Consortium for Frontotemporal Dementia; DWD was supported by P50NS072187, P50AG016574, State of Florida Alzheimer Disease Initiative, & CurePSP, Inc.; NRGR, JEP, RCP, DK, BFB were supported by P50 AG016574; KAJ was supported by R01 AG037491; WWS was supported by NIH AG023501, AG019724, Consortium for Frontotemporal Dementia Research; BLM was supported by P50AG023501, P01AG019724, Consortium for FTD Research; HR was supported by AG032306. JCvS was supported by Stichting Dioraphte Foundation (11 02 03 00), Nuts Ohra Foundation (0801-69), Hersenstichting Nederland (BG 2010-02) and Alzheimer Nederland. CG and HHC acknowledge families, patients, clinicians including Dr Inger Nennesmo and Dr Vesna Jelic, Professor Laura Fratiglioni for control samples and Jenny Björkström, Håkan Thonberg, Charlotte Forsell, Anna-Karin Lindström and Lena Lilius for sample handling. CG was supported by Swedish Brain Power (SBP), the Strategic Research Programme in Neuroscience at Karolinska Institutet (StratNeuro), the regional agreement on medical training and clinical research (ALF) between Stockholm County Council and Karolinska Institutet, Swedish Alzheimer Foundation, Swedish Research Council, Karolinska Institutet PhD-student funding, King Gustaf V and Queen Victoria’s Free Mason Foundation. FP, AR, VD and FL acknowledge Labex DISTALZ. RF acknowledges the help and support of Mrs. June Howard at the Texas Tech University Health Sciences Center Office of Sponsored Programs for tremendous help in managing Material Transfer Agreement at TTUHSC. UKBEC and NABEC members: Michael E Weale, Department of Medical and Molecular Genetics, King¹s College London, 8th Floor, Tower Wing, Guy¹s Hospital, London SE1 9RT, UK; Mina Ryten, Reta Lila Weston Institute and Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK; Adaikalavan Ramasamy, Department of Medical and Molecular Genetics, King¹s College London, 8th Floor, Tower Wing, Guy¹s Hospital, London SE1 9RT, UK, Reta Lila Weston Institute and Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK; Daniah Trabzuni, Reta Lila Weston Institute and Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK, Department of Genetics, King Faisal Specialist Hospital and Research Centre, PO Box 3354, Riyadh 11211, Saudi Arabia; Colin Smith, Department of Neuropathology, MRC Sudden Death Brain Bank Project, University of Edinburgh, Wilkie Building, Teviot Place, Edinburgh EH8 9AG; Robert Walker, Department of Neuropathology, MRC Sudden Death Brain Bank Project, University of Edinburgh, Wilkie Building, Teviot Place, Edinburgh EH8 9AG. Mark R Cookson, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA; J. Raphael Gibbs, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA, Reta Lila Weston Institute and Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK; Allissa Dillman, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA, Department of Neuroscience, Karolinska Institutet, 171 77 Stockholm, Sweden; Alan B Zonderman,

Research Resources Branch, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA; Sampath Arepalli, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA; Luigi Ferrucci, Clinical Research Branch, National Institute on Aging, Baltimore, MD, USA; Robert Johnson, NICHD Brain and Tissue Bank for Developmental Disorders, University of Maryland Medical School, Baltimore, Maryland 21201, USA; Dan L Longo, Lymphocyte Cell Biology Unit, Laboratory of Immunology, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA; Richard O'Brien, Brain Resource Center, Johns Hopkins University, Baltimore, MD, USA; Bryan Traynor, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA; Juan Troncoso, Brain Resource Center, Johns Hopkins University, Baltimore, MD, USA; Marcel van der Brug, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA, ITGR Biomarker Discovery Group, Genentech, South San Francisco, CA, USA; Ronald H Zielke, NICHD Brain and Tissue Bank for Developmental Disorders, University of Maryland Medical School, Baltimore, Maryland 21201, USA.

(Salpêtrière Hospital, Pierre & Marie Curie University, Paris, France); Florence Pasquier (Université Lille Nord de France, Lille, France); Dominique Campion (University of Rouen, France); Matthias Riemenschneider (Saarland University; University Hospital, Homburg/Saar, Germany); Markus Otto (Universitätsklinikum Ulm, Ulm, Germany); Adrian Danek (Ludwig-Maximilians-Universität and DZNE, Munich, Germany); Panos Alexopoulos (Technische Universität Münich, Münich, Germany); Matthis Synofzik (Hertie Institute for Clinical Brain Research and DZNE, Tübingen, Germany); Manuela Neumann (University of Tübingen,Tübingen, Germany); Alfredo Ramirez, Michael Heneka, Frank Jessen (University of Bonn and DZNE, Bonn, Germany); Rachel Sanchez-Valle (Alzheimer's disease and other cognitive disorders unit and Hospital Clínic, IDIBAPS, Barcelona, Spain); Jordi Clarimón (Universitat Autònoma de Barcelona, Barcelona and (CIBERNED), Madrid, Spain.); Ellen Gelpi (Biobanc-Hospital Clinic-Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, Spain); Merce Boada (Memory Clinic of Fundació ACE, Barcelona, Spain); Pau Pastor (Universidad de Navarra, and University of Navarra School of Medicine, Pamplona, and Instituto de Salud Carlos III, Madrid, Spain); Alexandre de Mendonça (University of Lisbon, Lisbon, Portugal); Isabel Santana (Centro Hospitalar Universitário de Coimbra, Coimbra and University of Coimbra, Coimbra, Portugal); Alessandro Padovani (University of Brescia, Brescia, Italy); Sandro Sorbi (NEUROFARBA, University of Florence, Florence, Italy); Giovanni Frisoni (LENITEM, IRCCS Fatebenefratelli, Brescia, Italy); Luisa Benussi (NeuroBioGen Lab-Memory Clinic, IRCCS Fatebenefratelli, Brescia, Italy); Maura Gallo (Regional Neurogenetic Centre, Lamezia Terme, Italy); Gian Maria Fabrizi (University of Verona, Verona, Italy); Gabor Kovacs (Medical University of Vienna, Vienna, Austria); Radek Matej (Thomayer Hospital and Charles University, Prague, Czech Republic); Maria Judit Molnar (Semmelweis University, Budapest, Hungary); Stayko Sarafov, Ivailo Tournev, Shima Mehrabian (Medical University Sofia, Sofia, Bulgaria); Jørgen Erik Nielsen, Gunhild Waldemar (Copenhagen University Hospital, Copenhagen, Denmark); Jørgen Erik Nielsen (The Panum Institute, University of Copenhagen, Copenhagen, Denmark); Michael Bjørn Petersen, Karsten Vestergård (Aalborg Hospital, Aalborg, Denmark); Caroline Graff (Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden); Mikko Hiltunen (University of Eastern Finland and Institute of Clinical Medicine, Kuopio, Finland ); Magda Tsolaki (Aristotle University of Thessaloniki, Thessaloniki, Greece.); Sermin Genc (University of Dokuz Eylul, Izmir, Turkey).

*Reply to Reviewers Comments

Reviewer #5: Generally the authors have responded appropriately. A few points remain to be addressed. Thank you

1. Reviewer 5 pt3. It is still not stated clearly why each case had some matched controls identified, since the final analysis was an unmatched analysis that included principal components to adjust for population structure. It seems that the individual matching was only done to allocate controls to the sub-type analysis such that there was no overlap across subtypes. The existing text is not clear enough on this.

We have now revised the text in the “Statistical methods and quality control – Discovery phase” section as follows: “After preliminary quality assessment, PCA as implemented in EIGENSTRAT22 was used to evaluate matching between cases and controls based on all available cases and controls. Custom coding in R was used to match cases to controls. Each subtype (bvFTD, SD, PNFA and FTD- MND) was treated as separate groups in which the two most genetically similar unique controls per case were selected based on eigenvectors 1 and 2. This was carried out to compensate for a lack of precisely matched controls at recruitment / study design. In this aspect, matched controls were unique per case and non-redundant across subtype datasets. Thus, cases and controls were matched for each subtype (bvFTD, SD, PNFA and FTD-MND) based on similarity of the first two eigenvectors from PCA and did not overlap across subtypes. Logistic regression was used based on imputed dosages to assess the association between each SNP and FTD or any of the FTD subtypes, adjusting for eigenvectors 1 and 2 from PCA as covariates. Eigenvectors were generated separately for each subtype, as in the overall sample pool, parameter estimates for the first 2 were associated with case status at p-values < 0·05. Fixed effects meta-analyses were performed to combine results across subtypes and quantify heterogeneity across subtypes.”. We believe to have now addressed this point and thank the reviewer for the opportunity to further clarify this.

2. Reviewer 5 pt8. It is clear that the effect allele is the one to which the OR applies. It is still unclear how the effect allele is chosen. It appears completely random and as such, is useless information.

Initially, the “effect alleles” were chosen based on the reference allele as per 1000 genomes release (August 2010). Now all effects have been flipped to the minor allele, and are as such presented in a revised version of Table 2.

3. The new text has a lot of grammatical errors and does not give the impression that all the authors have read and approved it. Please encourage all the authors, particularly the English speakers, to carefully proof the manuscript before submission.

I have read this through thoroughly “out loud” and I am pretty sure the few clumsy phrases have now been changed

4. P12 L8 what is the "bias" in the NeuroX asrray content?

Bias is towards GWAS hits, rare variants / functional mutations and other risk factors associated with a number of neurodegenerative diseases, as well as rare (MAF < 5%) coding variants (exonic content).

5. P12 L19 "an effort to minimize the limited power of this phase". I don't understand why you would want to minimize power.

This was a typo. We thank for the note. “Maximise” was meant and this has now been revised in the text.

6. P12 L21 not clear why 5 eigenvectors are used in the replication, but only 2 in the discovery.

Five eigenvectors were used in the replication phase due to pooled analysis with no a priori matching; two eigenvectors were used in discovery due to a priori matching of case controls based on preliminary analyses of genetic data.

7. P16 par2 please replace "r-squared" with a scientific notation. Clarify whether these r^2 refer to the imputation quality or the variance in outcome explained by the SNP.

The nomenclature “r-squared” was requested previously by another reviewer. This has now been updated to r2 in the results section and in Table 2. R2 represents the correlation coefficient that indicates the predictive LD between two loci.

8. P18 par2 "...an overall need during this work for robust statistical adjustments..." this is a standard aspect of GWAS and is not a specific limitation of the study, no need for this text. Your limitations relate more to phenotype heterogeneity, low prevalence (and therefore available sample size) and probably low heritability of the forms attributable to common variants.

We thank the reviewer for this point. We have revised this section as follows: “It needs to be acknowledged that a number of limitations may apply to this study. Given phenotype heterogeneity in the clinical presentation of FTD and considering that it is a rare neurodegenerative disorder (low prevalence),2 testing the hypothesis “common variant – common disease” for diseases of this kind is challenging and clearly benefits from large sample sizes. In addition, there was an overall need during this work for robust statistical adjustments to correct for potential confounding factors due to population stratification, cases and controls matching and for differences in arrays used to generate genotyping data during the discovery phase. Nevertheless, In addition, based on the nature of this study, our study may indicate association with specific loci without necessarily implying causality; low heritability due to common variability may also apply. However, importantly, the QQ plots and associated lambda values (Supplementary Figure SF1, webappendix pp 4) conformed to GWAS standards, supporting confidence in the final results, eventually.”

Figure Click here to download Figure: Figure 1a-e.pdf

Figure 1 a-e. Manhattan plots of −log10 p-values across genome identifying the regions with genome-wide significant associations. 1a. Manhattan plot for the entire dataset of the discovery phase depicts the associated region at 6p21.3. SNPs with smallest p-values and their location within or in proximity of the nearest genes are shown. 1b. Manhattan plot for the bvFTD of the discovery phase depicts the associated region at 11q14. SNPs with smallest p-values and their location within or in proximity of the nearest genes are shown. Further, Manhattan plots for each of the other subtypes are shown: although no SNPs reached genome wide significance across different chromosomes those that achieved p-values between 10-06 and 10-07 are shown for the SD (1c), PNFA (1d) and FTD-MND (1e) subtypes. Figure 1a

10# 9# 8# 7# 6#

Chromosome(6(

Chr6:32,360K# 32,380K# 32,400K# 32,420K# 32,440K# 32,460K# 32,480K# 32,500K#

rs1980493( rs9268856( rs9268877(

HLA)DRB5& BTNL2& HLA)DRA& Figure 1b

8# 7# 6#

Chromosome(11(

Chr11:87,850K# 87,900K# 87,950K# 88M# 88,050K# 88,050K#

rs302652( rs74977128(

CTSC& RAB38& Figure 1c

7# 6#

Figure 1d

8# 7# 6#

Figure 1e

7# 6# Figure ClickFigure here to 1a download Figure: FTD-GWAS_paper_Figure.pptx

10 9 8 7 6

Chromosome 6

Chr6:32,360K 32,380K 32,400K 32,420K 32,440K 32,460K 32,480K 32,500K

rs1980493 rs9268856 rs9268877

HLA-DRB5 BTNL2 HLA-DRA Figure 1b

8 7 6

Chromosome 11

Chr11:87,850K 87,900K 87,950K 88M 88,050K 88,050K

rs302652 rs74977128

CTSC RAB38 Figure 1c

7 6

Figure 1d

8 7 6

Figure 1e

7 6 Table

Table 1 1a. Samples that have been collected during the discovery and the replication phases and their characteristics are shown. The numbers of samples that have been included in analysis after the material QC are depicted; ° identifies the samples that survived genotyping data QC and that were used to perform actual association analyses. Also female percentages as well as mean age at onset for both discovery and replication cohorts are shown (per country and in total).

Samples Country Collected Included in analysis Females % (n) Mean age at onset

Discovery Replication Discovery Replication Total Total Discovery phase Replication phase Discovery phase Replication phase phase phase phase phase USA 706 209 915 579 175 754 44·4 (n=257/579) 48·9 (n=85/174) 60 (23-85; n=520) 63 (24-93; n=120)

Canada 25 37 62 24 29 53 52·2 (n=12/23) 57·1 (n=8/14) 64 (43-85; n=15) 59 (43-75; n=9)

UK 494 372 866 401 284 685 42·8 (n=171/400) 39·7 (n=108/272) 60 (23-83; n=372) 61 (35-86; n=167)

Spain 100 330 430 0 309 309 NA 43 (n=133/309) NA 65 (32-89; n=308)

France 238 54 292 205 42 247 44·4 (n=91/205) 47·6 (n=20/42) 62 (39-79; n=190) NA

Belgium 240 51 291 191 42 233 46·1 (n=88/191) 28·6 (n=12/42) 63 (29-90; n=191) 64 (43-84; n=42)

Netherlands 333 93 426 250 77 327 51·6 (n=129/250) 40·3 (n=31/77) 58 (29-76; n=250) 61 (51-69; n=59)

Denmark 35 0 35 7 0 7 71·4 (n=5/7) NA 57 (40-62; n=7) NA

Germany 349 34 383 320 33 353 NA 50 (n=15/30) 61 (36-83; n=243) 57 (29-72; n=30)

Sweden 26 112 138 18 98 116 55·6 (n=10/18) 61·2 (n=60/98) 57 (38-75; n=16) 62 (28-78; n=93)

Italy 1035 563 1598 564 371 935 52·9 (n=297/561) 45·3 (n=168/371) 64 (31-83; n=429) 65 (31-87; n=353)

Australia 0 138 138 0 121 121 NA 36·4 (n=44/121) NA 59 (32-77; n=112)

Meta 3,581 1,993 5,574 2,559 (2,154°) 1,581 (1,372°) 4,140 (3,526°) 46·5 (n=1,186/2,552) 44·1 (n=684/1,550) 61 (23-90; n=2,233) 62 (24-93; n=1,293)

Table

Table 1 1b. The number of samples collected per subtype and per country are shown; ° identifies the samples that survived genotyping data QC and that were used to perform actual association analyses.

Subtypes Country bvFTD SD PNFA FTD-MND FTLD-U Discovery Replication Discovery Replication Discovery Replication Discovery Replication Discovery Replication Total Total Total Total Total phase phase phase phase phase phase phase phase phase phase

USA 315 25 340 147 12 159 81 15 96 36 21 57 0 102 102

Canada 22 5 27 1 1 2 0 5 5 1 7 8 0 11 11

UK" 207 152 359 75 53 128 69 44 113 50 16 66 0 19 19

Spain NA 194 194 NA 41 41 NA 51 51 NA 13 13 NA 10 10

France 135 30 165 3 0 3 8 3 11 59 8 67 0 1 1

Belgium 135 27 162 13 1 14 22 2 24 21 2 23 0 10 10

Netherlands 159 37 196 47 31 78 24 6 30 20 3 23 0 0 0

Denmark 2 NA 2 0 NA 0 1 NA 1 4 NA 4 0 NA 0

Germany 209 18 227 45 8 53 55 6 61 11 1 12 0 0 0

Sweden 7 53 60 2 20 22 6 10 16 3 8 11 0 7 7

Italy 443 186 629 28 22 50 69 86 155 24 16 40 0 61 61

Australia" NA 56 56 NA 26 26 NA 19 19 NA 20 20 NA 0 0

Meta 1,634 (1,377°) 783 (690°) 2,417 (2,061°) 361 (308°) 215 (190°) 576 (495°) 335 (269°) 247 (221°) 582 (486°) 229 (200°) 115 (94°) 344 (294°) 0 (0) 221 (177°) 221 (177°)

" = sharing same controls

Table

Table 2 SNPs exceeding genome wide significance in discovery phase are listed along with their chromosomal position and nearby genes. Replication and joint analyses were assessed for the same SNPs at 6p21·3, whereas proxy SNPs were used to assess the association at 11q14 (for which r-squared values are included). The odds ratio (OR) is shown for the minor allele. Chr=chromosome; BP=base position; OR=odds ratio; SE=standard error; P=p-value; r2=correlation coefficient that indicates the predictive LD between two loci.

Discovery phase Trait Marker Chr BP Candidate gene Minor allele Major allele Frequency of minor allele Imputation quality OR (95% CI) SE P

rs302652 11 87894831 RAB38 A T 0.259 0·9296 0·730 (0·65-0·82) 0·057 2·02x10-8 bvFTD rs74977128 11 87936874 RAB38/CTSC C T 0·118 0·4182 1·815 (1·48-2·24) 0·107 3·06x10-8 rs9268877 6 32431147 HLA-DRA/HLA-DRB5 A G 0·440 0·7783 1·331 (1·22-1·45) 0·045 1·65x10-10 All FTD* rs9268856 6 32429719 HLA-DRA/HLA-DRB5 A C 0·251 0·8563 0·752 (0·68-0·83) 0·050 1·30x10-8

-8 rs1980493 6 32363215 BTNL2 C T 0·147 0·9642 0·720 (0·69-0·81) 0·060 4·94x10 Replication phase Marker Chr BP Candidate gene Minor allele Major allele Frequency of minor allele R-squared (r2) Imputation quality OR (95% CI) SE P

bvFTD rs302668 (proxy) 11 87876911 RAB38 C T 0.325 0·65 NA 0.877 (0.77-0.99) 0·064 0·041 rs16913634 (proxy) 11 87934068 RAB38/CTSC A G 0.104 0·54 NA 0.964 (0.79-1.17) 0·098 0·710

rs9268877 6 32431147 HLA-DRA/HLA-DRB5 A G 0.449 NA NA 1·080 (0·98-1·18) 0·047 0·104 All FTD* rs9268856 6 32429719 HLA-DRA/HLA-DRB5 A C 0.253 NA NA 0·878 (0·79-0·97) 0·053 0·014 rs1980493 6 32363215 BTNL2 C T 0.145 NA NA 0.85 (0·75-0·97) 0·068 0·020 Discovery and replication combined Marker Chr BP Candidate gene Minor allele Major allele Frequency of minor allele R-squared (r2) Imputation quality OR (95% CI) SE P

-7 rs302668 (proxy) 11 87876911 RAB38 C T 0.292 0·65 NA 0·814 (0·71-0·92) 0·064 2·44x10 bvFTD -4 rs16913634 (proxy)$ 11 87934068 RAB38/CTSC A G 0.111 0·54 NA 1·248 (1·14-1·37) 0·049 8·15x10 -8 rs9268877$ 6 32431147 HLA-DRA/HLA-DRB5 A G 0.4445 NA NA 1·204 (1·11-1·30) 0·039 1·05x10 All FTD* rs9268856 6 32429719 HLA-DRA/HLA-DRB5 A C 0.252 NA NA 0·809 (0·76-0·86) 0·029 5·51x10-9 -8 rs1980493 6 32363215 BTNL2 C T 0.146 NA NA 0·775 (0·69-0·86) 0·058 1·57x10

*denotes only minimal cross subtype heterogeneity, with heterogeneity p-values ranging from 0·793 - 0·944 based on Cochran's Q $ denotes heterogeneity p-value < 0·01 in the meta-analyse of the discovery and replication phases combined Table

Table 3 Summary of association of top hits with -cis methylation levels at 6p21·3. Association is shown for rs1980493 and rs9268877 suggestive of their implication in methylation processes and patterns in relation to HLA- DRA.

Frequency Effect estimate CpG Position Reference Alternate Imputation Standard FDR adjsuted Probe start Probe end Dataset SNP Chr of reference of alternate P-value Symbol probe (bp) allele allele quality error p-value (BP) (BP) allele allele (in Z units)

Frontal cortex - CpG cg21415604 rs1980493 6 32363215 T C 0·8361 0·9888 -0·463 0·116 0·0000701 0·00834666 31948433 31948483 C4B methylation Frontal cortex - CpG cg25764570 rs1980493 6 32363215 T C 0·8361 0·9888 -0·652 0·116 2·17x10-8 0·00000773 32407239 32407289 HLA-DRA methylation Frontal cortex - CpG cg25764570 rs9268856 6 32429719 C A 0·748 0·9687 -0·484 0·1 1·16x10-6 0·000207417 32407239 32407289 HLA-DRA methylation

Table

Table 4 Comparison between SNPs and loci associated with other conditions than FTD or other closely related conditions such as ALS, PSP/CBD and AD, and our study. P-values are shown for each different locus and OR is calculated for the same effect allele in all conditions and our study.

OTHER STUDIES OUR STUDY (discovery phase)

Imputation Gene/ SNP Reference Alternate Frequency of Reported Frequency of Meta (All Chr Disease Ref quality bvFTD SD PNFA FTD-MND nearby gene (bp) allele allele reference allele association reference allele FTD) (RSQ) P (joint) OR OR OR OR OR OR P P P P P (95% CI) (95% CI) (95% CI) (95% CI) (95% CI) rs8070723 0·950 (Stage 1); A G 1·50x10-116 5·46 0·765 0·8400 2·80x10-4 1·201 3·14x10-3 1·201 4·34x10-1 1·103 8·72x10-3 1·471 5·82x10-1 1·091 (44081064) 0·940 (Stage 2) (1·09-1·32) (1·06-1·36) (0·86-1·41) (1·10-1·97) (0·80-1·49) 17 PSP/CBD MAPT 40 rs242557 0·470 (Stage 1); 0·815 G A 4·20x10-70 0·51 0·634 0·5246 4·82x10-3 0·853 1·27x10-2 0·841 3·20x10-1 0·867 2·02x10-1 8·23x10-1 0·961 (44019712) 0·500 (Stage 2) (1·05-1·31) (0·73-0·96) (0·65-1·15) (0·59-1·11) (0·68-1·36) TOMM40/ rs2075650 19 AD G A 0·150 1·80x10-157 2·53 41 0·141 0·9978 8·81x10-7 1·304 1·37x10-6 1·383 3·64x10-2 1·326 8·69x10-1 0·976 2·06x10-1 1·252 APOE (45395619) (0·69-0·85) (0·63-0·82) (0·58-0·98) (0·76-1·38) (0·56-1·13) C9orf72/ rs3849942 9 ALS A G 0·260 1·01x10-8 1·20 39 0·253 0·9996 4·38x10-4 1·166 7·38x10-3 1·155 9·89x10-1 1·010 9·03x10-1 0·990 2·12x10-6 1·957 MOB3B (27543281) (1·07-1·27) (0·78-0·96) (0·80-1·25) (0·79-1·31) (0·39-0·68) rs1990622 A G 0·679 1·08x10-11 1·64 17 0·600 0·9588 7·88x10-2 1·080 5·85x10-3 1·144 8·36x10-1 0·978 8·98x10-1 0·985 3·11x10-1 0·876 (12283787) (0·99-1·16) (1·04-1·26) (0·80-1·20) (0·79-1·23) (0·68-1·13) FTLD- rs6966915 7 TMEM106B C T 0·679 1·63x10-11 1·64 17 0·596 0.9675 1·21x10-1 1·070 5·74x10-3 1·144 5·27x10-1 0·936 7·26x10-1 0·961 3·62x10-1 0·888 TDP (12265988) (0·87-1·02) (1·04-1·26) (0·76-1·15) (0·77-1·20) (0·69-1·14) rs1020004 T C 0·767 5·00x10-11 1·66 17 0·693 0.9538 4·59x10-1 1·030 5·71x10-2 1·104 8·53x10-1 0·980 5·00x10-1 0·921 1·20x10-1 0·805 (12255778) (0·95-1·12) (1·00-1·22) (0·79-1·21) (0·72-1·17) (0·61-1·06) rs1386330 MS RAB38 C T 0·130 2·00x10-6 NA 43 0·141 0·9694 3·35x10-1 1·050 6·09x10-1 1·040 7·60x10-1 1·040 6·97x10-1 1·060 3·00x10-1 0·829 (87819427) (0·85-1·06) (0·84-1·10) (0·72-1·27) (0·68-1·29) (0·58-1·18) rs3135388 A G 0·230 8·94x10-81 1·99 44 0·131 0·9734 4·80x10-2 1·122 2·10x10-1 1·095 1·25x10-1 1·254 5·02x10-1 1·120 6·10x10-1 1·105 (32413051) (1·00-1·26) (0·79-1·05) (0·60-1·06) (0·64-1·24) (0·61-1·33) 6 MS HLA-DRA rs3129871 A C 0·504 5·70x10-15 1·72 45 0·337 0·9379 3·43x10-1 0·961 3·15x10-1 0·949 4·94x10-1 1·078 8·24x10-1 0·974 2·72x10-1 0·859 (32406342) (0·88-1·04) (0·95-1·16) (0·75-1·15) (0·81-1·30) (0·89-1·53) rs3129882 PD HLA-DRA G A 0·450 1·90x10-10 1·26 46 0·456 0·9992 3·36x10-2 1·086 3·27x10-2 1·106 7·52x10-1 1·033 5·74x10-1 1·065 7·07x10-1 1·049 (32409530) (0·85-0·99) (0·82-0·99) (0·79-1·18) (0·75-1·17) (0·74-1·22)

Necessary Additional Data

Supplementary Table S1 List of PIs of collaborative sites that directly sent DNA samples to the three Institutions leading the project. The totality of the collaborative sites is listed in the authors and affiliations section of the manuscript.

Site PI Main Institutions Country Parastoo Momeni* Texas Tech University Health Sciences Center, Lubbock, Texas, USA USA/UK Caroline Graff Karolinska Institute, Department of NVS, Stockholm, Sweden SWEDEN Isabelle Leber* Unit of Research of Neurology and experimental Therapy, Paris, France FRANCE Jorgen Nielsen Section of Neurogenetics, University of Copenhagen, Denmark DENMARK Adrian Danek Department of Neurology, Ludwig-Maximilian University of Munich, Germany GERMANY Robert Perneczky Department of Psychiatry and Psychotherapy, Tech University Munich, Germany GERMANY Saarland University Hospital, Department for Psychiatry & Psychotherapy, Kirrberger Str.1, Bld.90, 66421 Matthias Riemenschneider* GERMANY Homburg/Saar, Germany Johannes Schlachetzki Memory Clinic, University Hospital, Freiburg, Germany GERMANY Barbara Borroni Department of Medical Sciences, Neurological Clinic, University of Brescia, Italy ITALY Annibale Puca* Gruppo Multimedica, Milan, Italy ITALY Giacomina Rossi Neurological Institute Carlo Besta, Milan, Italy ITALY Daniela Galimberti* Department of Neurological Sciences, Dino Ferrari Institute, University of Milan, Italy ITALY Innocenzo Rainero Department of Neuroscience, University of Torino, Italy ITALY Luisa Benussi NeuroBioGen Lab-Memory Clinic, Fatebenefratelli, Brescia, Italy ITALY Benedetta Nacmias Department of Neurological and Psychiatric Sciences, University of Florence, Italy ITALY Amalia Bruni Regional Center of Neurogenetic, Lamezia Terme, Italy ITALY Department of Basic Medical Sciences, Neurosciences and Sense Organs of the "Aldo Moro" University of Giancarlo Logroscino ITALY Bari, Italy Jonathan Rohrer Institute of Neurology, UCL, London, UK UK Simon Mead Institute of Neurology, Prion Unit, UCL, London, UK UK James Rowe Cambridge University Department of Clinical Neurosciences, Cambridge, CB2 0SZ UK Stuart Pickering-Brown* University of Manchester, Clinical Neuroscience, Manchester, UK UK Huw Morris Department of Neurology, Cardiff University School of Medicine, Cardiff, UK UK Ekaterina Roageva Center for research in Neurodegenerative diseases, Toronto, Canada CANADA Rosa Rademakers* Mayo Clinic Jacksonville, Florida, USA USA Vivianna Van Deerlin University of Pennsylvania Health System, Department of Pathology, Philadelphia, PA, USA USA Christine Van Broekhoven* Department of Molecular Genetics, University of Antwerp, Belgium BELGIUM Peter Heutink German Center of Neurodegenerative Diseases-Tübingen, Germany NETHERLANDS John van Swieten Department of Neurology, Erasmus Medical Center, Rotterdam, Netherlands NETHERLANDS Jordi Clarimon Genetics of Neurodegenerative Diseases Unit | IIB Hospital Sant Pau, Barcelona, Spain SPAIN

Pau Pastor Center for Applied Medical Research, Division of Neurology, University of Navarra, Pamplona, Spain SPAIN Carlos Cruchaga Department of Psychiatry, HPAN, WU, St. Louis, USA USA Ian Mackenzie Department of Pathology, Vancouver General Hospital, Vancouver, BC, Canada CANADA Maria Landqvist Unit of Geriatric Psychiatry, Department of Clinical Sciences, Lund University, Sweden SWEDEN Agustin Ruiz ACE Foundation. Catalan Institute of Applied Neuroscience, Barcelona, Spain SPAIN Peter Schofield Neuroscience Research Australia, Sydney, Australia AUSTRALIA * = PI representing multiple centers

Supplementary Table S2 Example of the spreadsheet used to collect data and characterize each collected sample.

Age Age Neuropsych Path data Sample Family Imaging data MAPT chr9 at at Gender Diagnosis data available available Proband ID MAPT PGRN TDP43 FUS CHMP2B APOE ID History available (y/n) hap repeats Onset Death (y/n) (y/n)

PNFA FTD- FTLD (in first degree (and supportive of (and supportive of (or from family (if other family 1, 11, 12, bvFTD SD (excluding all 10 MND unspecified relative) FTLD) FTLD) member) member included) 9 13 LPA cases)

Supplementary Figure SF1 Quantile-quantile (QQ) plots representative of observed (y axis) vs. expected (x axis) SNPs distribution. The lambda values for each QQ plot were as follows: bvFTD=1.036; SD=1.030; PNFA=1.023; FTD-MND=1.041; Meta=1.013.

Supplementary Table S3 All the 29 SNPs exceeding the genome wide significance threshold at 6p21·3 are shown. The OR is calculated based on the effect allele.

Heterogeneity Frequency Directionality Position Effect Alternate Standard p-value SNP Chr of effect Beta OR P-value across (BP) allele allele error (Cochrane's allele subtypes Q) rs9268877 6 32431147 A G 0.440 0.286 1.331 0.045 1.65x10-10 ++++ 0.8184 rs9268852 6 32429594 A G 0.439 0.280 1.323 0.044 1.68x10-10 ++++ 0.8242 rs9268863 6 32430289 A G 0.442 0.279 1.321 0.044 2.20x10-10 ++++ 0.8295 - rs9268881 6 32431606 A T 0.560 0.750 0.045 2.39x10-10 ---- 0.8102 0.288 - rs9268888 6 32431867 T G 0.556 0.740 0.048 2.99x10-10 ---- 0.645 0.302 - rs9268912 6 32432509 A C 0.559 0.741 0.048 3.88x10-10 ---- 0.7369 0.300 - rs9268883 6 32431638 A T 0.553 0.749 0.046 4.49x10-10 ---- 0.7834 0.289 - rs9268893 6 32431927 T C 0.539 0.748 0.048 1.42x10-9 ---- 0.721 0.290 - rs9268856 6 32429719 A C 0.251 0.752 0.050 1.30x10-8 ---- 0.9437 0.285 rs9268854 6 32429672 A G 0.752 0.288 1.334 0.051 1.47x10-8 ++++ 0.943 - rs9268855 6 32429675 A G 0.248 0.750 0.051 1.47x10-8 ---- 0.943 0.288 rs9268862 6 32430167 A C 0.750 0.284 1.328 0.050 1.48x10-8 ++++ 0.9426 - rs9268845 6 32429204 T C 0.240 0.744 0.052 1.48x10-8 ---- 0.97 0.295 rs9268857 6 32429739 A G 0.750 0.283 1.327 0.050 1.62x10-8 ++++ 0.9431 - rs9268850 6 32429477 A G 0.248 0.751 0.051 1.69x10-8 ---- 0.9431 0.286 - rs9268840 6 32428804 T C 0.246 0.753 0.051 2.06x10-8 ---- 0.9504 0.284 rs7747521 6 32431105 A G 0.761 0.303 1.353 0.054 2.26x10-8 ++++ 0.9374 - rs4434496 6 32430508 T C 0.249 0.749 0.052 2.31x10-8 ---- 0.941 0.289 rs4428528 6 32430362 C G 0.752 0.289 1.334 0.052 2.36x10-8 ++++ 0.9406 - rs7766843 6 32430729 T C 0.245 0.746 0.053 2.37x10-8 ---- 0.9421 0.293 rs6940440 6 32429087 A C 0.747 0.274 1.315 0.049 2.41x10-8 ++++ 0.9543 - rs7766854 6 32430752 T C 0.245 0.746 0.053 2.47x10-8 ---- 0.9425 0.293 rs7747010 6 32430800 A G 0.759 0.299 1.348 0.054 3.11x10-8 ++++ 0.9409 rs7747025 6 32430814 A G 0.759 0.299 1.348 0.054 3.11x10-8 ++++ 0.9409 - rs4280993 6 32430604 A C 0.249 0.749 0.052 3.20x10-8 ---- 0.9399 0.289 - rs7746751 6 32430867 A G 0.249 0.749 0.052 3.21x10-8 ---- 0.9398 0.289 - rs7746922 6 32430975 A C 0.245 0.747 0.053 3.82x10-8 ---- 0.9374 0.292 - rs9268885 6 32431705 T C 0.245 0.737 0.056 4.43x10-8 ---- 0.9275 0.305 rs1980493 6 32363215 T C 0.853 0.329 1.389 0.060 4.94x10-8 ++++ 0.793

Supplementary Table S4 Summary and statistics of all SNPs with p-values between 10-06 and 10-07 in each subtype and in the entire cohort (meta-analysis).

Frequency Imputation Effect Alternate Cases Controls MARKER Chr Bp of effect quality Beta OR SE P-value allele allele (N) (N) allele (RSQ ) rs3025144 7 24273159 C A 0.9821 0.3945 1.67 5.314 0.344 1.80E-07 1377 2754 rs12800378 11 87865942 T C 0.6794 0.9119 0.266 1.305 0.053 4.81E-07 1377 2754 rs2565116 8 40267939 C T 0.7282 0.9829 0.276 1.317 0.055 5.00E-07 1377 2754 rs302668 11 87876911 T C 0.6703 0.9736 0.254 1.289 0.051 5.78E-07 1377 2754 rs302660 11 87885448 A G 0.6719 0.982 0.253 1.288 0.051 5.88E-07 1377 2754 rs302647 11 87908346 C G 0.6856 0.8012 0.285 1.330 0.058 5.98E-07 1377 2754 chr11:87879075 11 87879075 C T 0.6708 0.9814 0.251 1.286 0.051 6.73E-07 1377 2754 rs302662 11 87881236 A G 0.6745 0.9561 0.255 1.291 0.052 6.82E-07 1377 2754 rs302644 11 87913471 G T 0.6927 0.7652 0.291 1.338 0.059 7.07E-07 1377 2754 chr19:45394336 19 45394336 T C 0.8567 0.9607 -0.336 0.714 0.068 7.60E-07 1377 2754 rs769449 19 45410002 G A 0.8784 0.8335 -0.382 0.683 0.077 7.61E-07 1377 2754 rs956686 8 40275938 T C 0.7435 0.931 0.283 1.327 0.058 8.10E-07 1377 2754 rs586689 11 87919481 C T 0.6783 0.7524 0.287 1.332 0.059 9.45E-07 1377 2754 rs9268852 6 32429594 G A 0.561 0.822 -0.26 0.771 0.054 1.12E-06 1377 2754 rs302663 11 87880759 T C 0.6678 0.9691 0.247 1.280 0.051 1.15E-06 1377 2754 rs11822961 11 87934579 A G 0.9002 0.6676 -0.449 0.639 0.092 1.18E-06 1377 2754 bvFTD rs9268863 6 32430289 G A 0.5576 0.8128 -0.261 0.770 0.054 1.18E-06 1377 2754 rs9268877 6 32431147 G A 0.5598 0.7783 -0.267 0.766 0.055 1.21E-06 1377 2754 rs9268881 6 32431606 A T 0.5599 0.7657 -0.268 0.765 0.056 1.28E-06 1377 2754 rs1223545 6 13161879 C T 0.7824 0.9407 0.291 1.338 0.061 1.30E-06 1377 2754 chr11:87934330 11 87934330 T C 0.8976 0.669 -0.44 0.644 0.09 1.34E-06 1377 2754 rs16913634 11 87934068 G A 0.8976 0.6701 -0.44 0.644 0.09 1.36E-06 1377 2754 rs2075650 19 45395619 A G 0.8589 0.9978 -0.325 0.723 0.067 1.37E-06 1377 2754 rs6857 19 45392254 C T 0.8383 0.8585 -0.33 0.719 0.068 1.39E-06 1377 2754 rs11556505 19 45396144 C T 0.8618 0.9663 -0.332 0.717 0.068 1.40E-06 1377 2754 rs7256200 19 45415935 G T 0.8753 0.7059 -0.4 0.670 0.082 1.40E-06 1377 2754 rs7111593 11 87933128 G A 0.8972 0.669 -0.439 0.645 0.09 1.42E-06 1377 2754 rs34404554 19 45395909 C G 0.8601 0.9818 -0.328 0.721 0.068 1.42E-06 1377 2754 rs10414043 19 45415713 G A 0.876 0.6906 -0.404 0.667 0.083 1.47E-06 1377 2754 rs1223544 6 13161490 G A 0.7854 0.9242 0.293 1.341 0.062 1.51E-06 1377 2754 chr8:40248352 8 40248352 T C 0.7145 0.9838 0.259 1.296 0.054 1.51E-06 1377 2754 rs649221 11 87928710 G C 0.6631 0.7064 0.286 1.331 0.06 1.58E-06 1377 2754

rs1223547 6 13167258 G T 0.7859 0.9387 0.291 1.337 0.061 1.58E-06 1377 2754 rs1386328 11 87907674 C T 0.908 0.8033 -0.415 0.660 0.086 1.72E-06 1377 2754 rs7106306 11 87929167 C G 0.8975 0.6948 -0.427 0.652 0.089 1.77E-06 1377 2754 chr11:87928479 11 87928479 T C 0.8975 0.696 -0.427 0.653 0.089 1.78E-06 1377 2754 chr11:87928476 11 87928476 T C 0.8975 0.6964 -0.426 0.653 0.089 1.79E-06 1377 2754 rs34342646 19 45388130 G A 0.8627 0.7623 -0.373 0.689 0.078 1.83E-06 1377 2754 rs7942323 11 87927204 C T 0.8975 0.7041 -0.423 0.655 0.088 1.91E-06 1377 2754 chr11:87927258 11 87927258 T C 0.8975 0.7037 -0.423 0.655 0.088 1.91E-06 1377 2754 rs7947723 11 87927052 A G 0.8975 0.7049 -0.422 0.656 0.088 1.94E-06 1377 2754 rs11018798 11 87926055 C T 0.8975 0.7065 -0.421 0.656 0.088 1.98E-06 1377 2754 rs9268845 6 32429204 C T 0.7598 0.8305 0.3 1.349 0.064 2.01E-06 1377 2754 rs12972970 19 45387596 G A 0.8634 0.759 -0.372 0.689 0.078 2.05E-06 1377 2754 rs9268883 6 32431638 A T 0.5525 0.7284 -0.269 0.764 0.057 2.08E-06 1377 2754 chr11:87925840 11 87925840 A G 0.893 0.6954 -0.417 0.659 0.087 2.18E-06 1377 2754 rs9268888 6 32431867 T G 0.5564 0.6794 -0.278 0.757 0.059 2.30E-06 1377 2754 rs12106377 21 33248175 C T 0.6212 0.5875 -0.297 0.743 0.063 2.33E-06 1377 2754 rs8129628 21 33248173 T G 0.613 0.5889 -0.296 0.744 0.063 2.33E-06 1377 2754 rs12972156 19 45387459 C G 0.8672 0.7384 -0.379 0.684 0.08 2.37E-06 1377 2754 rs11018787 11 87919202 C T 0.9008 0.7212 -0.419 0.657 0.088 2.42E-06 1377 2754 rs1223541 6 13159891 C T 0.7731 0.9148 0.284 1.329 0.061 2.49E-06 1377 2754 rs11018796 11 87922954 A C 0.8973 0.7309 -0.41 0.664 0.086 2.50E-06 1377 2754 rs1228529 6 13161138 T C 0.7765 0.9489 0.278 1.320 0.06 2.55E-06 1377 2754 rs7104717 11 87921900 A G 0.8973 0.7331 -0.409 0.664 0.086 2.55E-06 1377 2754 rs1385513 4 168150594 A C 0.8223 0.8882 -0.3 0.741 0.064 2.64E-06 1377 2754 rs12233248 2 16020757 A G 0.5915 0.842 0.246 1.279 0.053 2.67E-06 1377 2754 rs405509 19 45408836 G T 0.5314 0.9992 -0.22 0.802 0.047 2.72E-06 1377 2754 rs9268912 6 32432509 A C 0.5593 0.6713 -0.278 0.757 0.059 2.78E-06 1377 2754 rs10119 19 45406673 G A 0.7307 0.674 -0.299 0.742 0.064 2.82E-06 1377 2754 rs157585 19 45397512 C A 0.4798 0.8969 -0.232 0.793 0.05 2.92E-06 1377 2754 rs302669 11 87876812 T C 0.651 0.9812 0.234 1.263 0.05 3.05E-06 1377 2754 rs10128715 11 87872076 G A 0.9142 0.9449 -0.382 0.683 0.081 3.19E-06 1377 2754 rs157588 19 45398264 C T 0.5213 0.895 0.231 1.260 0.05 3.22E-06 1377 2754 rs157584 19 45396899 C T 0.4854 0.8692 -0.235 0.791 0.051 3.24E-06 1377 2754 rs34886409 2 16000384 C T 0.544 0.8693 0.236 1.266 0.051 3.27E-06 1377 2754 rs1359526 10 3390982 G A 0.6067 0.8982 -0.237 0.789 0.051 3.29E-06 1377 2754 chr11:87932479 11 87932479 T A 0.9032 0.6528 -0.439 0.645 0.094 3.37E-06 1377 2754 rs10128567 11 87871776 T C 0.9157 0.9257 -0.387 0.679 0.083 3.60E-06 1377 2754 rs11685493 2 16003716 A G 0.5393 0.8936 0.231 1.260 0.05 3.61E-06 1377 2754

rs302645 11 87916672 C T 0.6499 0.8268 0.253 1.288 0.055 3.67E-06 1377 2754 rs11695239 2 16002683 C T 0.5387 0.8905 0.231 1.260 0.05 3.67E-06 1377 2754 rs157590 19 45398716 C A 0.4834 0.8802 -0.231 0.794 0.05 3.73E-06 1377 2754 rs1385515 4 168150827 A G 0.8037 0.852 -0.29 0.748 0.063 3.78E-06 1377 2754 rs17440578 2 15999451 C T 0.5395 0.8612 0.235 1.265 0.051 3.82E-06 1377 2754 rs34653314 2 16026869 T C 0.6337 0.9425 0.233 1.263 0.051 3.85E-06 1377 2754 rs1385514 4 168150818 A G 0.8023 0.8446 -0.291 0.748 0.063 3.87E-06 1377 2754 rs11018780 11 87914332 C T 0.8973 0.7833 -0.388 0.678 0.083 3.89E-06 1377 2754 rs55751005 2 15987324 C T 0.5548 0.6055 0.281 1.325 0.061 3.91E-06 1377 2754 rs12052368 2 16025675 T A 0.6594 0.8668 0.247 1.280 0.054 4.03E-06 1377 2754 rs1386327 11 87871538 A G 0.9157 0.9232 -0.386 0.680 0.083 4.04E-06 1377 2754 rs4669008 2 15993755 T G 0.5542 0.6724 0.266 1.305 0.058 4.06E-06 1377 2754 rs13387967 2 15992051 A C 0.5542 0.669 0.267 1.306 0.058 4.06E-06 1377 2754 rs9268840 6 32428804 C T 0.7539 0.8645 0.281 1.324 0.062 4.14E-06 1377 2754 rs12278560 11 87879800 A G 0.915 0.9525 -0.377 0.686 0.081 4.18E-06 1377 2754 rs2380684 2 15998357 G A 0.5628 0.7847 0.247 1.281 0.054 4.19E-06 1377 2754 rs12277605 11 87910542 C G 0.8972 0.7958 -0.384 0.681 0.083 4.29E-06 1377 2754 rs9268850 6 32429477 G A 0.7516 0.8607 0.279 1.322 0.062 4.41E-06 1377 2754 rs35780614 2 16026688 A G 0.6266 0.9224 0.234 1.263 0.051 4.51E-06 1377 2754 rs9268854 6 32429672 A G 0.7519 0.8439 0.282 1.326 0.062 4.53E-06 1377 2754 rs9268856 6 32429719 C A 0.7488 0.8563 0.279 1.321 0.061 4.54E-06 1377 2754 rs7102810 11 87908216 G A 0.9035 0.8352 -0.383 0.682 0.083 4.54E-06 1377 2754 rs9268855 6 32429675 G A 0.7518 0.8433 0.282 1.326 0.062 4.55E-06 1377 2754 rs16913378 11 87884293 T C 0.9093 0.9407 -0.368 0.692 0.08 4.58E-06 1377 2754 rs36115018 2 16027843 T C 0.7006 0.8773 0.255 1.290 0.056 4.63E-06 1377 2754 rs11678237 2 15986586 C A 0.5625 0.565 0.29 1.336 0.064 4.69E-06 1377 2754 rs9268857 6 32429739 A G 0.75 0.8615 0.277 1.320 0.061 4.84E-06 1377 2754 rs9268862 6 32430167 A C 0.75 0.8591 0.278 1.320 0.061 4.87E-06 1377 2754 rs9268893 6 32431927 T C 0.5386 0.6767 -0.268 0.765 0.059 4.95E-06 1377 2754 rs429358 19 45411941 T C 0.8676 0.7194 -0.364 0.695 0.079 5.04E-06 1377 2754 rs7128388 11 87929585 G T 0.7393 0.7081 -0.286 0.751 0.062 5.05E-06 1377 2754 rs7747521 6 32431105 A G 0.7606 0.7615 0.298 1.348 0.066 5.25E-06 1377 2754 rs6940440 6 32429087 A C 0.7471 0.8952 0.27 1.310 0.06 5.36E-06 1377 2754 rs12294982 11 87878379 G A 0.9126 0.9785 -0.363 0.695 0.079 5.51E-06 1377 2754 rs2380683 2 15992113 T C 0.5652 0.6423 0.27 1.310 0.06 5.57E-06 1377 2754 rs35214773 11 87882293 G T 0.9126 0.9765 -0.363 0.695 0.079 5.61E-06 1377 2754 rs12282553 11 87918451 C T 0.8932 0.7497 -0.385 0.681 0.084 5.67E-06 1377 2754 rs7114446 11 87886025 G A 0.9126 0.9718 -0.364 0.695 0.08 5.68E-06 1377 2754

rs4428528 6 32430362 C G 0.752 0.8141 0.283 1.327 0.063 6.02E-06 1377 2754 rs56067055 11 87897704 G A 0.8852 0.8864 -0.341 0.711 0.075 6.02E-06 1377 2754 chr19:45427125 19 45427125 T A 0.8418 0.3064 -0.518 0.595 0.114 6.13E-06 1377 2754 rs35514109 11 87863638 C T 0.9124 0.9468 -0.368 0.692 0.081 6.20E-06 1377 2754 rs4434496 6 32430508 C T 0.7513 0.8063 0.284 1.328 0.063 6.22E-06 1377 2754 rs4280993 6 32430604 C A 0.7513 0.8052 0.284 1.328 0.064 6.23E-06 1377 2754 chr19:45428234 19 45428234 G A 0.8379 0.302 -0.517 0.597 0.114 6.28E-06 1377 2754 rs7746751 6 32430867 G A 0.7512 0.8025 0.284 1.329 0.064 6.32E-06 1377 2754 rs11691710 2 16021097 T C 0.6249 0.9678 0.223 1.250 0.05 6.41E-06 1377 2754 rs7766843 6 32430729 C T 0.755 0.7887 0.288 1.334 0.064 6.41E-06 1377 2754 rs7766854 6 32430752 C T 0.755 0.7882 0.288 1.334 0.064 6.43E-06 1377 2754 rs7747025 6 32430814 A G 0.7592 0.7682 0.293 1.340 0.066 6.57E-06 1377 2754 rs7747010 6 32430800 A G 0.7592 0.7688 0.293 1.340 0.066 6.59E-06 1377 2754 rs7259620 19 45407788 G A 0.5357 0.9114 0.221 1.248 0.049 6.67E-06 1377 2754 rs35875238 11 87891401 G A 0.8223 0.8911 0.293 1.340 0.066 6.72E-06 1377 2754 rs1038026 19 45405062 A G 0.5354 0.9185 0.22 1.246 0.049 6.77E-06 1377 2754 rs7746922 6 32430975 C A 0.7546 0.7875 0.287 1.333 0.065 6.80E-06 1377 2754 rs3117097 6 32358689 A G 0.8514 0.9768 0.324 1.383 0.073 6.82E-06 1377 2754 rs741780 19 45404431 T C 0.5357 0.92 0.22 1.246 0.049 6.82E-06 1377 2754 rs1038025 19 45404972 T C 0.5394 0.9036 0.222 1.248 0.05 6.99E-06 1377 2754 rs1980493 6 32363215 T C 0.8529 0.9642 0.328 1.388 0.074 7.02E-06 1377 2754 rs144601873 17 51511109 C T 0.9843 0.3676 1.824 6.194 0.462 7.04E-06 1377 2754 rs760136 19 45403858 A G 0.5355 0.9197 0.22 1.246 0.049 7.06E-06 1377 2754 rs7943882 11 87917670 G A 0.7374 0.8149 -0.26 0.771 0.058 7.24E-06 1377 2754 rs4233847 2 16013712 G A 0.6265 0.9543 0.223 1.250 0.05 7.45E-06 1377 2754 rs3129953 6 32361821 C T 0.8515 0.9756 0.323 1.381 0.073 7.83E-06 1377 2754 rs9268861 6 32429894 C A 0.7903 0.7615 0.308 1.361 0.07 7.99E-06 1377 2754 rs11682632 2 16018901 G A 0.6298 0.9479 0.224 1.251 0.05 8.05E-06 1377 2754 rs11688136 2 16010659 A C 0.6242 0.9675 0.22 1.246 0.05 8.42E-06 1377 2754 rs62065288 17 26756768 T C 0.7814 0.3137 0.465 1.593 0.106 8.48E-06 1377 2754 rs1160985 19 45403412 C T 0.531 0.9025 0.219 1.245 0.05 8.60E-06 1377 2754 rs1223538 6 13158099 G A 0.7766 0.8994 0.272 1.313 0.062 8.71E-06 1377 2754 rs6850485 4 168150023 T C 0.8108 0.9374 -0.27 0.763 0.061 8.86E-06 1377 2754 rs9268878 6 32431292 T A 0.7609 0.7476 0.293 1.340 0.067 9.04E-06 1377 2754 rs9268879 6 32431306 T G 0.76 0.7505 0.292 1.339 0.066 9.08E-06 1377 2754 rs7687091 4 168139333 C T 0.8122 0.9663 -0.266 0.766 0.06 9.41E-06 1377 2754 rs9268886 6 32431828 G A 0.7535 0.7034 0.298 1.347 0.068 9.60E-06 1377 2754 rs9268885 6 32431705 C T 0.7548 0.7087 0.297 1.346 0.068 9.64E-06 1377 2754

rs9268894 6 32431954 T G 0.7914 0.5549 0.355 1.426 0.081 9.78E-06 1377 2754 rs3129959 6 32375796 A T 0.8512 0.986 0.317 1.373 0.073 9.81E-06 1377 2754 rs2395158 6 32374595 A G 0.851 0.9846 0.317 1.373 0.073 9.85E-06 1377 2754 rs12534802 7 21197432 G A 0.8236 0.9619 0.711 2.035 0.145 2.80E-07 308 616 chr7:21188129 7 21188129 A T 0.8241 0.9477 0.71 2.035 0.146 3.63E-07 308 616 rs17737414 7 21192755 T A 0.8251 0.9462 0.713 2.041 0.147 3.63E-07 308 616 rs4028683 15 25037506 G T 0.811 0.7435 -0.741 0.476 0.149 6.36E-07 308 616 rs61855879 10 56386287 C T 0.9771 0.4656 -2.283 0.102 0.497 7.71E-07 308 616 rs2192058 7 21173828 G T 0.8276 0.853 0.731 2.078 0.155 8.84E-07 308 616 rs12538434 7 21178262 C T 0.8261 0.8916 0.711 2.036 0.151 8.98E-07 308 616 rs11770862 7 21173046 G A 0.8291 0.8409 0.737 2.090 0.157 9.53E-07 308 616 rs12908563 15 25036840 T C 0.7784 0.8006 -0.66 0.517 0.136 1.15E-06 308 616 chr15:25037275 15 25037275 G A 0.7836 0.7911 -0.663 0.515 0.138 1.45E-06 308 616 rs12908397 15 25036766 T C 0.7827 0.8248 -0.641 0.527 0.135 1.82E-06 308 616 rs11762716 7 21184260 C T 0.8658 0.8608 0.768 2.155 0.169 1.93E-06 308 616 rs544087 7 79910081 C G 0.6065 0.8216 -0.528 0.590 0.113 2.71E-06 308 616 rs13206018 6 32663497 C T 0.8844 0.972 -0.706 0.494 0.151 2.74E-06 308 616 chr6:32663259 6 32663259 C T 0.8895 0.9134 -0.741 0.477 0.159 2.99E-06 308 616 chr10:113491268 10 113491268 A G 0.9734 0.6958 -1.726 0.178 0.381 3.03E-06 308 616 chr6:32663340 6 32663340 G A 0.8897 0.9221 -0.734 0.480 0.158 3.28E-06 308 616 SD rs62242438 3 38766348 T C 0.7374 0.9839 0.55 1.733 0.122 3.51E-06 308 616 chr12:29404202 12 29404202 G A 0.9823 0.3141 5.638 281.034 1.557 3.52E-06 308 616 rs17427431 6 32663644 G A 0.8928 0.9012 -0.753 0.471 0.163 3.52E-06 308 616 rs35122881 6 32663677 C T 0.8928 0.9014 -0.753 0.471 0.163 3.52E-06 308 616 rs9998937 4 134051803 C T 0.5348 0.8771 -0.508 0.602 0.111 3.59E-06 308 616 rs8029431 15 25036636 A C 0.6625 0.5812 -0.646 0.524 0.14 3.62E-06 308 616 rs17206182 6 32665504 C T 0.9075 0.7923 -0.849 0.428 0.184 3.63E-06 308 616 rs35770795 4 134044634 T C 0.5307 0.8773 -0.506 0.603 0.111 3.82E-06 308 616 rs13134791 4 134046253 C T 0.5327 0.9116 -0.496 0.609 0.109 3.82E-06 308 616 rs7664058 4 134045974 C T 0.5291 0.8966 -0.5 0.606 0.11 3.87E-06 308 616 rs906471 4 134050408 A G 0.5325 0.8968 -0.5 0.607 0.11 3.92E-06 308 616 rs62311794 4 134048304 C T 0.5547 0.9847 -0.478 0.620 0.105 3.96E-06 308 616 rs4404561 4 134046930 C A 0.5564 0.9983 -0.474 0.622 0.104 4.04E-06 308 616 rs4263412 4 134046923 A G 0.5564 0.9976 -0.474 0.622 0.104 4.06E-06 308 616 rs55642621 4 134043414 A G 0.5551 0.9426 -0.488 0.614 0.107 4.07E-06 308 616 rs2419947 4 134049961 C G 0.5561 0.974 -0.48 0.619 0.105 4.07E-06 308 616 rs1507837 4 134052358 G T 0.5558 0.956 -0.484 0.616 0.106 4.10E-06 308 616 rs55681333 4 134044660 T A 0.5537 0.9532 -0.485 0.616 0.106 4.10E-06 308 616

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rs1834499 3 139680323 A G 0.055 N/A 0.3927 1.481 0.0835 2.55E-06 2,154 4,308 chr3:139714685 3 139714685 T C 0.0522 N/A 0.3971 1.488 0.0845 2.60E-06 2,154 4,308 rs9767620 6 32426100 T C 0.9164 N/A 0.5091 1.664 0.1084 2.67E-06 2,154 4,308 chr3:139705342 3 139705342 T C 0.9477 N/A -0.3966 0.673 0.0845 2.71E-06 2,154 4,308 chr3:139714328 3 139714328 T C 0.9478 N/A -0.3963 0.673 0.0845 2.71E-06 2,154 4,308 rs7383481 6 32414435 T C 0.1116 N/A -0.3796 0.684 0.081 2.77E-06 2,154 4,308 chr3:139704173 3 139704173 A G 0.9477 N/A -0.3962 0.673 0.0845 2.78E-06 2,154 4,308 chr3:139706363 3 139706363 A C 0.0522 N/A 0.3957 1.485 0.0844 2.78E-06 2,154 4,308 rs9268932 6 32433290 T G 0.528 N/A 0.2771 1.319 0.0591 2.80E-06 2,154 4,308 chr3:139711510 3 139711510 T C 0.9479 N/A -0.3956 0.673 0.0845 2.83E-06 2,154 4,308 chr18:55734650 18 55734650 T C 0.9379 N/A -0.5462 0.579 0.1167 2.84E-06 2,154 4,308 rs58528760 3 139707719 T C 0.9479 N/A -0.3945 0.674 0.0844 2.98E-06 2,154 4,308 chr3:139710064 3 139710064 T G 0.052 N/A 0.3942 1.483 0.0844 3.00E-06 2,154 4,308 rs1834498 3 139693440 A G 0.0563 N/A 0.3961 1.486 0.0849 3.07E-06 2,154 4,308 rs10734641 11 9057657 A G 0.5321 N/A -0.2018 0.817 0.0433 3.20E-06 2,154 4,308 chr3:139653972 3 139653972 T C 0.0555 N/A 0.4025 1.496 0.0865 3.25E-06 2,154 4,308 chr3:139716710 3 139716710 A G 0.0502 N/A 0.4113 1.509 0.0884 3.28E-06 2,154 4,308 chr3:139706398 3 139706398 T G 0.9499 N/A -0.4073 0.665 0.0876 3.35E-06 2,154 4,308 rs3135371 6 32386699 A G 0.8707 N/A 0.3137 1.368 0.0676 3.52E-06 2,154 4,308 rs56131196 19 45422846 A G 0.1777 N/A 0.384 1.468 0.0828 3.54E-06 2,154 4,308 rs302652 11 87894831 A T 0.259 N/A -0.2149 0.807 0.0464 3.61E-06 2,154 4,308 rs36115018 2 16027843 T C 0.7006 N/A 0.2108 1.235 0.0455 3.66E-06 2,154 4,308 rs2330 3 139655773 A C 0.944 N/A -0.3996 0.671 0.0864 3.75E-06 2,154 4,308 rs3135353 6 32392877 T C 0.1274 N/A -0.3121 0.732 0.0676 3.83E-06 2,154 4,308 rs3129965 6 32380830 C G 0.1708 N/A -0.2546 0.775 0.0551 3.84E-06 2,154 4,308 rs2894255 6 32390332 T C 0.14 N/A -0.2889 0.749 0.0628 4.16E-06 2,154 4,308 rs1125686 3 139670763 A T 0.9429 N/A -0.3847 0.681 0.0836 4.22E-06 2,154 4,308 rs6984249 8 118082317 A G 0.2718 N/A 0.2328 1.262 0.0507 4.45E-06 2,154 4,308 rs35875446 8 118082017 A G 0.7243 N/A -0.2357 0.790 0.0514 4.51E-06 2,154 4,308 rs7000505 8 118078798 T G 0.7297 N/A -0.2356 0.790 0.0515 4.77E-06 2,154 4,308 rs1834502 3 139650242 A G 0.0588 N/A 0.392 1.480 0.0858 4.85E-06 2,154 4,308 chr12:53759858 12 53759858 T C 0.0187 N/A 0.8235 2.278 0.1803 4.97E-06 2,154 4,308 rs11685493 2 16003716 A G 0.5393 N/A 0.186 1.204 0.0408 5.05E-06 2,154 4,308 rs16889402 8 118113304 A G 0.2632 N/A 0.1986 1.220 0.0436 5.13E-06 2,154 4,308 rs11695239 2 16002683 T C 0.4613 N/A -0.1857 0.831 0.0408 5.21E-06 2,154 4,308 rs7017296 8 118078256 A G 0.7275 N/A -0.2341 0.791 0.0514 5.24E-06 2,154 4,308 rs7611408 3 139576524 A G 0.0396 N/A 0.479 1.614 0.1052 5.29E-06 2,154 4,308 rs7748925 6 32416983 T G 0.1048 N/A -0.3952 0.674 0.0869 5.38E-06 2,154 4,308

rs12679500 8 118087616 A G 0.2667 N/A 0.2265 1.254 0.0498 5.43E-06 2,154 4,308 rs2452444 16 73744310 T C 0.9135 N/A -0.362 0.696 0.0796 5.50E-06 2,154 4,308 rs3129963 6 32380208 A G 0.8284 N/A 0.2495 1.283 0.055 5.62E-06 2,154 4,308 rs11989800 8 118096610 A C 0.714 N/A -0.2198 0.803 0.0485 5.72E-06 2,154 4,308 rs17440578 2 15999451 T C 0.4605 N/A -0.1882 0.828 0.0415 5.86E-06 2,154 4,308 rs34886409 2 16000384 T C 0.456 N/A -0.1878 0.829 0.0415 5.89E-06 2,154 4,308 rs4420638 19 45422946 A G 0.8195 N/A -0.372 0.689 0.0823 6.19E-06 2,154 4,308 rs2467442 16 73744419 T C 0.0886 N/A 0.3562 1.428 0.0789 6.29E-06 2,154 4,308 rs1505527 8 118090119 C G 0.7149 N/A -0.2217 0.801 0.0491 6.40E-06 2,154 4,308 chr3:139648996 3 139648996 T C 0.943 N/A -0.3868 0.679 0.0857 6.43E-06 2,154 4,308 rs12800378 11 87865942 T C 0.6794 N/A 0.1962 1.217 0.0436 6.64E-06 2,154 4,308 rs633687 11 87936024 A G 0.7382 N/A 0.2454 1.278 0.0545 6.65E-06 2,154 4,308 rs12721051 19 45422160 C G 0.8244 N/A -0.3616 0.697 0.0806 7.31E-06 2,154 4,308 rs57686953 8 118105854 A G 0.7258 N/A -0.2051 0.815 0.0458 7.56E-06 2,154 4,308 rs9268880 6 32431358 T G 0.3486 N/A 0.1967 1.217 0.044 7.64E-06 2,154 4,308 rs7776297 6 32424108 T C 0.0819 N/A -0.4888 0.613 0.1095 8.10E-06 2,154 4,308 rs6469673 8 118095630 T C 0.7185 N/A -0.2187 0.804 0.049 8.12E-06 2,154 4,308 rs10505293 8 118084951 A G 0.2656 N/A 0.226 1.254 0.0507 8.14E-06 2,154 4,308 rs302668 11 87876911 T C 0.6703 N/A 0.1866 1.205 0.0418 8.15E-06 2,154 4,308 rs3135394 6 32408497 A G 0.8937 N/A 0.3471 1.415 0.0778 8.21E-06 2,154 4,308 rs11783033 8 109628271 T C 0.2379 N/A 0.3032 1.354 0.068 8.24E-06 2,154 4,308 rs2227138 6 32384500 T C 0.1394 N/A -0.2804 0.755 0.0629 8.27E-06 2,154 4,308 rs10743098 11 9059550 A G 0.4678 N/A 0.1952 1.216 0.0439 8.84E-06 2,154 4,308 rs11042158 11 9054161 T C 0.4373 N/A 0.1912 1.211 0.0431 9.00E-06 2,154 4,308 rs11989353 8 118080721 A G 0.714 N/A -0.2251 0.798 0.0507 9.07E-06 2,154 4,308 rs7821939 8 118092105 A T 0.282 N/A 0.2177 1.243 0.0491 9.26E-06 2,154 4,308 chr12:53773299 12 53773299 A G 0.9814 N/A -0.9333 0.393 0.2107 9.47E-06 2,154 4,308 rs9469119 6 32427155 A C 0.0921 N/A -0.4517 0.637 0.102 9.51E-06 2,154 4,308 rs9985239 3 139643881 A G 0.0578 N/A 0.3817 1.465 0.0863 9.65E-06 2,154 4,308 rs9469118 6 32427154 T G 0.908 N/A 0.4509 1.570 0.102 9.93E-06 2,154 4,308

Supplementary Table S5 Summary and statistics of effects on expression exerted by rs302652.

SNP probe_id ILMN_Gene snp_probe_distance p-value

rs302652 ILMN_2134974 RAB38 312,176 5.05x10-32

Supplementary Table S6 Summary of frequency of C9orf72 positive cases within the discovery cohort shown for each subtype separately and the totality of samples (C9orf72 repeat expansion screening was performed in various labs participating in this study including [Ref. 14 of main text]).

Discovery phase

bvFDT SD PNFA FTD-MND Total C9orf 72+ n+/nS % n+/nS % n+/nS % n+/nS % n+/nS % 121/1537 7.9 12/350 3.4 9/304 3.0 52/221 23.5 194/2412 8.0

n+ = number of cases positive for the repeat expansion nS = number of cases screened