A genome-wide linkage and association scan reveals novel loci for autism (original) (raw)

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Acknowledgements

We thank all of the families who have participated in and contributed to the public resources that we have used in these studies. The Broad Institute Center for Genotyping and Analysis is supported by grant U54 RR020278 from the National Center for Research Resources. The Gene Discovery Project of Johns Hopkins was funded by grants from the National Institutes of Mental Health (MH60007, MH081754) and the Simons Foundation. This study was funded in part through a grant from the Autism Consortium of Boston. Support for the Extreme Discordant Sib-Pair (EDSP) family sample was provided by the NLM Family foundation. Support for the Massachusetts General Hospital (MGH)–Finnish collaborative sample was provided by NARSAD. Support for the Homozygosity Mapping Collaborative for Autism (HMCA) came from NIMH (1R01 MH083565), the Nancy Lurie Marks (NLM) Family Foundation and the Simons Foundation. Eric M. Morrow is supported by the NIMH (1K23MH080954). Support for the Iranian family sample was provided by the Special Education Organization of Iran, under the Iranian Ministry of Education. Lauren A. Weiss was supported by a Ruth L. Kirschstein National Research Service Award and is currently supported by the International Mental Health Research Organization. The collection of data and biomaterials that participated in the National Institute of Mental Health (NIMH) Autism Genetics Initiative has been supported by National Institute of Health grants MH52708, MH39437, MH00219 and MH00980; National Health Medical Research Council grant 0034328; and by grants from the Scottish Rite, the Spunk Fund, Inc., the Rebecca and Solomon Baker Fund, the APEX Foundation, the National Alliance for Research in Schizophrenia and Affective Disorders (NARSAD), and the endowment fund of the Nancy Pritzker Laboratory (Stanford); and by gifts from the Autism Society of America, the Janet M. Grace Pervasive Developmental Disorders Fund, and families and friends of individuals with autism. The NIMH collection Principal Investigators and Co-Investigators were: Neil Risch, Richard M. Myers, Donna Spiker, Linda J. Lotspeich, Joachim F. Hallmayer, Helena C. Kraemer, Roland D. Ciaranello, Luigi Luca Cavalli-Sforza (Stanford University, Stanford); William M. McMahon and P. Brent Petersen (University of Utah, Salt Lake City). The Stanford team is indebted to the parent groups and clinician colleagues who referred families and extends their gratitude to the families with individuals with autism who were partners in this research. The collection data and biomaterials also come from the Autism Genetic Resource Exchange (AGRE) collection. This program has been supported by a National Institute of Health grant MH64547 and the Cure Autism Now Foundation. The AGRE collection Principal Investigator is Daniel H. Geschwind (UCLA). The Co-Principal Investigators include Stanley F. Nelson and Rita M. Cantor (UCLA), Christa Lese Martin (Univ. Chicago), T. Conrad Gilliam (Columbia). Co-Investigators include Maricela Alarcon (UCLA), Kenneth Lange (UCLA), Sarah J. Spence (UCLA), David H. Ledbetter (Emory) and Hank Juo (Columbia). Scientific oversight of the AGRE program is provided by a steering committee (Chair: Daniel H. Geschwind; Members: W. Ted Brown, Maja Bucan, Joseph D. Buxbaum, T. Conrad Gilliam, David Greenberg, David H. Ledbetter, Bruce Miller, Stanley F. Nelson, Jonathan Pevsner, Carol Sprouse, Gerard D. Schellenberg and Rudolph Tanzi). The Autism Genome Project (AGP) work was supported by the following grants: (1) The Hilibrand Foundation (Principal Investigator Joachim F. Hallmayer); (2) Autism Speaks (for the AGP); (3) grants from the National Institutes of Health (NIH) MH61009 (James S. Sutcliffe), MH55135 (Susan E. Folstein), MH55284 (Joseph Piven), HD055782 (Ellen M. Wijsman), NS042165 (Joachim F. Hallmayer); (4) Fundação para a Ciência e Tecnologia (POCTI/39636/ESP/2001) Fundação Calouste Gulbenkian (Astrid Vincente); (5) INSERM, Fondation de France, Fondation Orange, Fondation pour la Recherche Médicale (Catalina Betancur, Marion Leboyer), and the Swedish Science Council (Christopher Gillberg); (6) The Seaver Foundation (Joseph D. Buxbaum); (7) The Children’s Medical & Research Foundation (CMRF), Our Lady’s Children’s Hospital, Crumlin, Ireland (Sean Ennis); (8) The Medical Research Council (MRC) (Anthony P. Monaco, Anthony J. Bailey). Fresh-frozen brain tissue samples were obtained through the Autism Tissue Program and the Harvard Brain Bank.

Author Contributions L.A.W., D.E.A., M.J.D. and A. Chakravarti led design and execution of joint scan analyses and manuscript writing. Johns Hopkins University–NIMH genome scan team: D.E.A. and A. Chakravarti led study design and analysis of scan; C.W.B. and E.H.C. provided evaluation of phenotype data, phenotype definition from primary data and editing of the manuscript; K. West, A.O’C. and G.H. conducted primary and replication genotyping with allele calling; R.L.T. and A.B.W. performed expression analysis and editing of the manuscript. Autism Consortium–AGRE genome scan team: L.A.W., T.G. and M.J.D. performed data processing and analysis for the genome-wide association scan; S-C.C., E.M.H., E.M.M., R.S. and S.L.S. provided evaluation of phenotype data and phenotype definition from primary data; S.G., C. Gates, C. Sougnez and C. Stevens led the genotyping team; A.K., J.K., F.K., S.M., B.N. and S.P. performed and evaluated allele calling and advised the analysis; M.J.D., L.A.W., R.T., P.S., S.L.S., J. Gusella and D.A. designed and initiated the study and provided manuscript comments and edits. Replication teams: each replication team provided genotypes, phenotypes and analysis of top ranking SNPs from the combined genome-wide association scan and contributed comments during manuscript preparation.

Author information

Author notes

  1. Lauren A. Weiss
    Present address: Present addresses: Department of Psychiatry, Institute for Human Genetics, Center for Neurobiology and Psychiatry, UCSF, San Francisco, California, USA (L.A.W.); Department of Molecular Biology, Cell Biology and Biochemistry, and Institute for Brain Science, Brown University, Providence, Rhode Island, USA (E.M.M.).,
  2. Annemarie Poustka: Deceased.
  3. Lauren A. Weiss and Dan E. Arking: These authors contributed equally to this work.

Authors and Affiliations

  1. Center for Human Genetic Research, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA.,
    Lauren A. Weiss, Mark J. Daly, Lauren A. Weiss, Todd Green, Shun-Chiao Chang, Andrew Kirby, Joshua Korn, Finny Kuruvilla, Steven McCarroll, Eric M. Morrow, Benjamin Neale, Shaun Purcell, Roksana Sasanfar, David Altshuler, James Gusella, Susan L. Santangelo, Pamela Sklar, Rudolph Tanzi, Mark J. Daly, Eric M. Morrow, David Pauls, Roksana Sasanfar, Susan L. Santangelo, Kara Andresen, Brian Winkloski & Stephen Haddad
  2. Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.,
    Lauren A. Weiss, Mark J. Daly, Lauren A. Weiss, Todd Green, Stacey Gabriel, Casey Gates, Andrew Kirby, Joshua Korn, Finny Kuruvilla, Steven McCarroll, Eric M. Morrow, Benjamin Neale, Shaun Purcell, Carrie Sougnez, Christine Stevens, David Altshuler, James Gusella, Pamela Sklar, Mark J. Daly, Eric M. Morrow, Seung-Yun Yoo, Robert Sean Hill & Christopher A. Walsh
  3. Center for Complex Disease Genomics, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University, Baltimore, Maryland 21205, USA.,
    Dan E. Arking, Aravinda Chakravarti, Dan E. Arking, Kristen West, Ashley O’Connor, Gina Hilton & Aravinda Chakravarti
  4. Department of Psychiatry, Institute for Juvenile Research, University of Illinois at Chicago, Chicago, Illinois 60612, USA.,
    Camille W. Brune, Edwin H. Cook Jr, Stephen J. Guter, Bennett L. Leventhal, Nancy J. Minshew & Jeff Salt
  5. Center for Neurodegeneration and Experimental Therapeutics, University of Alabama School of Medicine, Birmingham, Alabama 35294, USA.,
    Rebecca L. Tomlinson, Andrew B. West, Ellen M. Hanson & Edwin H. Cook Jr
  6. Developmental Medicine Center, Children’s Hospital Boston, Boston, Massachusetts 02115, USA.,
    Janice Ware, Elaine LeClair, Ellen M. Hanson, Rachel Hundley & Leonard A. Rappaport
  7. Division of Genetics, Children’s Hospital Boston and Harvard Medical School, Boston, Massachusetts 02115, USA.,
    Eric M. Morrow, Eric M. Morrow, Seung-Yun Yoo, Robert Sean Hill, Jennifer N. Partlow, Brenda Barry, Christopher A. Walsh, Lou Kunkel, Zak Kohane, Tram Tran, Sek Won Kong, Stephanie Brewster O’Neil, Ingrid Holm, Heather Peters, Elizabeth Baroni, Aislyn Cangialose, Lindsay Jackson, Lisa Albers, Ronald Becker, Carolyn Bridgemohan, Sandra Friedman, Kerim Munir, Ramzi Nazir, Judith Palfrey, Alison Schonwald & Esau Simmons
  8. Special Education Organization, Tehran, Iran.,
    Roksana Sasanfar, Roksana Sasanfar, Ala Tolouei, Majid Ghadami, Azam Hosseinipour & Maryam Valujerdi
  9. Department of Psychiatry, University of Oxford, Warneford Hospital, Headington, Oxford OX3 7JX, UK.,
    Anthony J. Bailey, Magdalena Laskawiec, Jeremy R. Parr, Katy Renshaw & Simon Wallace
  10. Newcomen Centre, Guy’s Hospital, London SE1 9RT, UK.,
    Gillian Baird
  11. Battelle Center for Mathematical Medicine, The Research Institute at Nationwide Children’s Hospital and The Ohio State University, Columbus, Ohio 43205, USA.,
    Veronica J. Vieland
  12. Child and Adolescent Mental Health, University of Newcastle, Sir James Spence Institute, Newcastle upon Tyne NE1 4LP, UK.,
    Tom Berney, Ann Le Couteur & Helen McConachie
  13. INSERM U952, Université Pierre et Marie Curie, 75005 Paris, France.,
    Catalina Betancur
  14. Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, J.W. Goethe University Frankfurt, 60528 Frankfurt, Germany.,
    Sven Bölte, Eftichia Duketis, Christine M. Freitag & Fritz Poustka
  15. Department of Child and Adolescent Psychiatry, Institute of Psychiatry, London SE5 8AF, UK.,
    Patrick F. Bolton
  16. Autism Research Unit, The Hospital for Sick Children and Bloorview Kids Rehabilitation, University of Toronto, Toronto, Ontario M5G 1Z8, Canada.,
    Jessica Brian, Xiao-Qing Liu, Andrew D. Paterson & Wendy Roberts
  17. Department of Pediatrics and Psychology, Dalhousie University, Halifax, Nova Scotia B3K 6R8, Canada.,
    Susan E. Bryson
  18. Departments of Psychiatry, Laboratory of Molecular Neuropsychiatry, Seaver Autism Center for Research and Treatment, Genetics and Genomic Sciences, and Neuroscience, Mount Sinai School of Medicine, New York, New York 10029, USA.,
    Joseph D. Buxbaum, Guiqing Cai & Jennifer Reichert
  19. Department of Human Genetics, University of California–Los Angeles School of Medicine, Los Angeles, California 90095, USA.,
    Rita M. Cantor
  20. Psychiatry Department, University of Utah Medical School, Salt Lake City, Utah 84108, USA.,
    Hilary Coon, William M. McMahon & Judith Miller
  21. Autism and Communicative Disorders Centre, University of Michigan, Ann Arbor, Michigan 48104, USA.,
    Christina Corsello, Vanessa Hus & Catherine Lord
  22. Miami Institute for Human Genomics, University of Miami, Miami, Florida 33136, USA.,
    Michael L. Cuccaro, John Gilbert & Margaret A. Pericak-Vance
  23. Departments of Psychology and Psychiatry, University of Washington, Seattle, Washington 98195, USA.,
    Annette Estes & Jeff Munson
  24. Department of Child Psychiatry, University Medical Center, Utrecht 3508 GA, The Netherlands.,
    Maretha de Jonge & Herman Van Engeland
  25. University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 19104-6100, USA.,
    Bernie Devlin
  26. School of Medicine and Medical Science University College, Dublin 4, Ireland.,
    Judith Conroy, Sean Ennis, Andrew Green & Regina Regan
  27. Division of Psychiatry, McGill University, Montreal, Quebec H3A 1A1, Canada.,
    Eric Fombonne, Ridha Joober & Eric Fombonne
  28. Department of Psychiatry, Autism Genetics Group, School of Medicine, Trinity College, Dublin 8, Ireland.,
    Richard Anney, Louise Gallagher, Michael Gill & Katherine Tansey
  29. Department of Neurology, University of California–Los Angeles School of Medicine, Los Angeles, California 90095, USA.,
    Daniel H. Geschwind
  30. Department of Psychiatry and Behavioural Neurosciences, McMaster University, Hamilton, Ontario L8N 3Z5, Canada.,
    Jeremy Goldberg, Peter Szatmari & Ann P. Thompson
  31. Academic Department of Child Psychiatry, Booth Hall of Children’s Hospital, Blackley, Manchester M9 7AA, UK.,
    Jonathan Green
  32. Centre for Human Genetics Research, Vanderbilt University Medical Centre, Nashville, Tennessee 37232, USA.,
    Jonathan L. Haines
  33. Child and Adolescent Psychiatry and Child Development, Stanford University School of Medicine, Stanford, California 94304, USA.,
    Joachim F. Hallmayer & Linda J. Lotspeich
  34. Deutsches Krebsforschungszentrum, Molekulare Genomanalyse, 69120 Heidelberg, Germany.,
    Sabine M. Klauck & Annemarie Poustka
  35. Centre for Integrated Genomic Medical Research, University of Manchester, Manchester M13 9PT, UK.,
    Janine A. Lamb
  36. Department of Pediatrics, McMaster University, Hamilton, Ontario L8S 3Z5, Canada.,
    William Mahoney
  37. Centre d’Eudes et de Recherches en Psychopathologie, University de Toulouse Le Miral, Toulouse 31058, France.,
    Carine Mantoulan, Bernadette Roge & Kerstin Wittemeyer
  38. Wellcome Trust Centre for Human Genetics, University of Oxford, OX3 7BN, UK.,
    Penny Farrar, Anthony P. Monaco, Alistair Pagnamenta & Kirsty Wing
  39. University Department of Child Psychiatry, Athens University, Medical School, Agia Sophia Children’s Hospital, Athens 115, Greece.,
    Katerina Papanikolaou & John Tsiantis
  40. Department of Medicine, School of Epidemiology and Health Science, University of Manchester, Manchester M13 9PT, UK.,
    Andrew Pickles
  41. Carolina Institute for Developmental Disabilities, University of North Carolina, Chapel Hill, North Carolina 27599-3366, USA.,
    Joseph Piven
  42. Social, Genetic and Developmental Psychiatry Centre, Institute Of Psychiatry, London SE5 8AF, UK.,
    Michael L. Rutter
  43. Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19108, USA.,
    Gerard D. Schellenberg
  44. The Hospital for Sick Children and Department of Molecular Genetics, The Centre for Applied Genomics and Program in Genetics and Genome Biology, University of Toronto, Toronto, Ontario M5G 1L7, Canada.,
    Xiao-Qing Liu, Christian R. Marshall, Andrew D. Paterson, Dalila Pinto & Stephen W. Scherer
  45. Department of Pediatrics and Howard Hughes Medical Institute Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242, USA.,
    Val Sheffield
  46. Vanderbilt Kennedy Center and Center for Molecular Neuroscience, Vanderbilt University, Nashville, Tennessee 37232, USA.,
    Emily L. Crawford, James S. Sutcliffe & Brian L. Yaspan
  47. Child Study Centre, Yale University, New Haven, Connecticut 06510, USA.,
    Fred Volkmar
  48. Department of Psychiatry, Carver College of Medicine, Iowa City, Iowa 52242, USA.,
    Thomas H. Wassink
  49. Department of Biostatistics and Medicine, University of Washington, Seattle, Washington 98195, USA.,
    Ellen M. Wijsman
  50. Department of Pediatrics, University of Alberta, Edmonton, Alberta T6G 2J3, Canada.,
    Lonnie Zwaigenbaum
  51. Instituto Nacional de Saude Dr Ricardo Jorge Instituto Gulbenkian de Cîencia Lisbon, 1600-560 Portugal.,
    Ines Cabrito, Catarina Correia, Tiago Magalhaes & Astrid M. Vicente
  52. Hospital Pediatrico de Coimbra, Coimbra, 3000-300 Portugal.,
    Guiomar Oliveira
  53. Department of Child and Adolescent Psychiatry, Goteborg University, Goteborg S41345, Sweden.,
    Christopher Gillberg
  54. Department of Psychiatry, INSERM U995, Groupe hospitalier Henri Mondor-Albert Chenevier, AP-HP, Créteil, France.,
    Marion Leboyer
  55. Department of Medicine, University of Washington, Seattle, Washington 98195, USA.,
    Olena Korvatska
  56. Department of Child and Adolescent Neurosciences, Stella Maris Institute, 56018 Calambrone (Pisa), Italy.,
    Agatino Battaglia
  57. Department of Psychiatry, Indiana University School of Medicine, Indianapolis 46202, USA.,
    Christopher J. McDougle, John I. Nurnberger Jr & David J. Posey
  58. Department of Biology, University of Bologna, 40126 Bologna, Italy.,
    Elena Maestrini
  59. Autism Speaks, New York, New York 10016, USA ,
    Geraldine Dawson
  60. Department of Neurology and Howard Hughes Medical Institute, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215, USA.,
    Eric M. Morrow, Eric M. Morrow, Seung-Yun Yoo, Robert Sean Hill, Jennifer N. Partlow, Brenda Barry & Christopher A. Walsh
  61. Department of Child Psychiatry, Istanbul Faculty of Medicine, Istanbul University, 34452 Istanbul, Turkey.,
    Nahit M. Mukaddes
  62. Department of Neurosciences and Pediatrics, King Faisal Specialist Hospital and Research Centre, Jeddah 11211, Kingdom of Saudi Arabia.,
    Soher Balkhy & Generoso Gascon
  63. Clinical Neurosciences & Pediatrics, Brown University School of Medicine, Providence, Rhode Island, USA.,
    Generoso Gascon
  64. Department of Neurology, Combined Military Hospital, Lahore, Pakistan.,
    Asif Hashmi
  65. Kuwait Center for Autism, Kuwait City 73455, Kuwait.,
    Samira Al-Saad
  66. Department of Anatomy and Neurobiology, Boston University School of Medicine, Boston, Massachusetts 02118, USA.,
    Robert M. Joseph
  67. Department of Child Psychiatry and Department of Clinical Genetics, Oulu University Hospital and Oulu University, Oulu FIN-90029, Finland.,
    Irma Moilanen, Hanna Ebeling, Marja-Leena Mattila, Sanna Kuusikko, Katja Jussila & Jaakko Ignatius
  68. Medical Genetic Diagnosis Department, National Institute for Genetic Engineering and Biotechnology, Tehran, Iran.,
    Maryam Rostami
  69. Casa de Corazon, Taos, New Mexico 87571, USA.,
    Kara Andresen
  70. Centre de recherche du CHUM, Hôpital Notre-Dame, Montréal, H2L 4M1 Quebec, Canada.,
    Julie Gauthier
  71. Sainte-Justine Hospital Research Center, Universite de Montreal, Montreal, H3T 1C5 Quebec, Canada.,
    Laurent Mottron & Guy Rouleau
  72. Department of Medical Genetics, University of Helsinki, Helsinki, FIN-00014, Finland.,
    Karola Rehnstrom, Lennart von Wendt & Leena Peltonen
  73. Department of Molecular Medicine, National Public Health Institute, Helsinki, FIN-00014, Finland.,
    Karola Rehnstrom, Lennart von Wendt & Leena Peltonen
  74. Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK.,
    Leena Peltonen

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  1. Lauren A. Weiss
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  2. Dan E. Arking
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The Gene Discovery Project of Johns Hopkins & the Autism Consortium

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Correspondence toMark J. Daly, Aravinda Chakravarti, Aravinda Chakravarti or Mark J. Daly.

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[Competing Interests: Aravinda Chakravarti is a paid member of the Scientific Advisory Board of Affymetrix, a role that is managed by the Committee on Conflict of Interest of the Johns Hopkins University School of Medicine.]

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Weiss, L., Arking, D. & The Gene Discovery Project of Johns Hopkins & the Autism Consortium. A genome-wide linkage and association scan reveals novel loci for autism.Nature 461, 802–808 (2009). https://doi.org/10.1038/nature08490

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