1. Center for Human Genetic Research, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA.
2. Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.
3. Center for Complex Disease Genomics, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University, Baltimore, Maryland 21205, USA.
4. Institute for Juvenile Research, Department of Psychiatry, University of Illinois at Chicago, Chicago, Illinois 60612, USA.
5. Center for Neurodegeneration and Experimental Therapeutics, University of Alabama School of Medicine, Birmingham, Alabama 35294, USA.
6. Developmental Medicine Center, Children's Hospital Boston, Boston, Massachusetts 02115, USA.
7. Division of Genetics, Children's Hospital Boston and Harvard Medical School, Boston, Massachusetts 02115, USA.
8. Special Education Organization, Tehran, Iran.
9. Department of Psychiatry, University of Oxford, Warneford Hospital, Headington, Oxford OX3 7JX, UK.
10. Newcomen Centre, Guy's Hospital, London SE1 9RT, UK.
11. Battelle Center for Mathematical Medicine, The Research Institute at Nationwide Children's Hospital and The Ohio State University, Columbus, Ohio 43205, USA.
12. Child and Adolescent Mental Health, University of Newcastle, Sir James Spence Institute, Newcastle upon Tyne NE1 4LP, UK.
13. INSERM U952, Université Pierre et Marie Curie, 75005 Paris, France.
14. Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, J.W. Goethe University Frankfurt, 60528 Frankfurt, Germany.
15. Department of Child and Adolescent Psychiatry, Institute of Psychiatry, London SE5 8AF, UK.
16. Autism Research Unit, The Hospital for Sick Children and Bloorview Kids Rehabilitation, University of Toronto, Toronto, Ontario M5G 1Z8, Canada.
17. Department of Pediatrics and Psychology, Dalhousie University, Halifax, Nova Scotia B3K 6R8, Canada.
18. Laboratory of Molecular Neuropsychiatry, Seaver Autism Center for Research and Treatment, Departments of Psychiatry, Genetics and Genomic Sciences, and Neuroscience, Mount Sinai School of Medicine, New York, New York 10029, USA.
19. Department of Human Genetics, University of California–Los Angeles School of Medicine, Los Angeles, California 90095, USA.
20. Psychiatry Department, University of Utah Medical School, Salt Lake City, Utah 84108, USA.
21. Autism and Communicative Disorders Centre, University of Michigan, Ann Arbor, Michigan 48104, USA.
22. Miami Institute for Human Genomics, University of Miami, Miami, Florida 33136, USA.
23. Departments of Psychology and Psychiatry, University of Washington, Seattle, Washington 98195, USA.
24. Department of Child Psychiatry, University Medical Center, Utrecht 3508 GA, The Netherlands.
25. University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 19104-6100, USA.
26. School of Medicine and Medical Science University College, Dublin 4, Ireland.
27. Division of Psychiatry, McGill University, Montreal, Quebec H3A 1A1, Canada.
28. Autism Genetics Group, Department of Psychiatry, School of Medicine, Trinity College, Dublin 8, Ireland.
29. Department of Neurology, University of California–Los Angeles School of Medicine, Los Angeles, California 90095, USA.
30. Department of Psychiatry and Behavioural Neurosciences, McMaster University, Hamilton, Ontario L8N 3Z5, Canada.
31. Academic Department of Child Psychiatry, Booth Hall of Children's Hospital, Blackley, Manchester M9 7AA, UK.
32. Centre for Human Genetics Research, Vanderbilt University Medical Centre, Nashville, Tennessee 37232, USA.
33. Child and Adolescent Psychiatry and Child Development, Stanford University School of Medicine, Stanford, California 94304, USA.
34. Deutsches Krebsforschungszentrum, Molekulare Genomanalyse, 69120 Heidelberg, Germany.
35. Centre for Integrated Genomic Medical Research, University of Manchester, Manchester M13 9PT, UK.
36. Department of Pediatrics, McMaster University, Hamilton, Ontario L8S 3Z5, Canada.
37. Centre d'Eudes et de Recherches en Psychopathologie, University de Toulouse Le Miral, Toulouse 31058, France.
38. Wellcome Trust Centre for Human Genetics, University of Oxford, OX3 7BN, UK.
39. University Department of Child Psychiatry, Athens University, Medical School, Agia Sophia Children's Hospital, Athens 115, Greece.
40. Department of Medicine, School of Epidemiology and Health Science, University of Manchester, Manchester M13 9PT, UK.
41. Carolina Institute for Developmental Disabilities, University of North Carolina, Chapel Hill, North Carolina 27599-3366, USA.
42. Social, Genetic and Developmental Psychiatry Centre, Institute Of Psychiatry, London SE5 8AF, UK.
43. Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19108, USA.
44. The Centre for Applied Genomics and Program in Genetics and Genome Biology, The Hospital for Sick Children and Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5G 1L7, Canada.
45. Department of Pediatrics and Howard Hughes Medical Institute Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242, USA.
46. Vanderbilt Kennedy Center and Center for Molecular Neuroscience, Vanderbilt University, Nashville, Tennessee 37232, USA.
47. Child Study Centre, Yale University, New Haven, Connecticut 06510, USA.
48. Department of Psychiatry, Carver College of Medicine, Iowa City, Iowa 52242, USA.
49. Department of Biostatistics and Medicine, University of Washington, Seattle, Washington 98195, USA.
50. Department of Pediatrics, University of Alberta, Edmonton, Alberta T6G 2J3, Canada.
51. Instituto Nacional de Saude Dr Ricardo Jorge Instituto Gulbenkian de Cîencia Lisbon, 1600-560 Portugal.
52. Hospital Pediatrico de Coimbra, Coimbra, 3000-300 Portugal.
53. Department of Child and Adolescent Psychiatry, Goteborg University, Goteborg S41345, Sweden.
54. INSERM U995, Department of Psychiatry, Groupe hospitalier Henri Mondor-Albert Chenevier, AP-HP, Créteil, France.
55. Department of Medicine, University of Washington, Seattle, Washington 98195, USA.
56. Stella Maris Institute, Department of Child and Adolescent Neurosciences, 56018 Calambrone (Pisa), Italy.
57. Department of Psychiatry, Indiana University School of Medicine, Indianapolis 46202, USA.
58. Department of Biology, University of Bologna, 40126 Bologna, Italy.
59. Autism Speaks, New York, New York 10016, USA
60. Department of Neurology and Howard Hughes Medical Institute, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215, USA.
61. Department of Child Psychiatry, Istanbul Faculty of Medicine, Istanbul University, 34452 Istanbul, Turkey.
62. Department of Neurosciences and Pediatrics, King Faisal Specialist Hospital and Research Centre, Jeddah 11211, Kingdom of Saudi Arabia.
63. Clinical Neurosciences & Pediatrics, Brown University School of Medicine, Providence, Rhode Island, USA.
64. Department of Neurology, Combined Military Hospital, Lahore, Pakistan.
65. Kuwait Center for Autism, Kuwait City 73455, Kuwait.
66. Department of Anatomy and Neurobiology, Boston University School of Medicine, Boston, Massachusetts 02118, USA.
67. Department of Child Psychiatry and Department of Clinical Genetics, Oulu University Hospital and Oulu University, Oulu FIN-90029, Finland.
68. Medical Genetic Diagnosis Department, National Institute for Genetic Engineering and Biotechnology, Tehran, Iran.
69. Casa de Corazon, Taos, New Mexico 87571, USA.
70. Centre de recherche du CHUM, Hôpital Notre-Dame, Montréal, H2L 4M1 Quebec, Canada.
71. Sainte-Justine Hospital Research Center, Universite de Montreal, Montreal, H3T 1C5 Quebec, Canada.
72. Department of Medical Genetics, University of Helsinki, Helsinki, FIN-00014, Finland.
73. Department of Molecular Medicine, National Public Health Institute, Helsinki, FIN-00014, Finland.
74. Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK.
75. 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.).
76. Deceased.
77. These authors contributed equally to this work.
78. Lists of participants and affiliations appears at the end of the paper.

Correspondence to: Correspondence and requests for materials should be addressed to A.C. (Email: aravinda@jhmi.edu) or M.J.D. (Email: mjdaly@chgr.mgh.harvard.edu).

Abstract

Although autism is a highly heritable neurodevelopmental disorder, attempts to identify specific susceptibility genes have thus far met with limited success¹. Genome-wide association studies using half a million or more markers, particularly those with very large sample sizes achieved through meta-analysis, have shown great success in mapping genes for other complex genetic traits. Consequently, we initiated a linkage and association mapping study using half a million genome-wide single nucleotide polymorphisms (SNPs) in a common set of 1,031 multiplex autism families (1,553 affected offspring). We identified regions of suggestive and significant linkage on chromosomes 6q27 and 20p13, respectively. Initial analysis did not yield genome-wide significant associations; however, genotyping of top hits in additional families revealed an SNP on chromosome 5p15 (between SEMA5A and TAS2R1) that was significantly associated with autism (P = 2  10^-7). We also demonstrated that expression of SEMA5A is reduced in brains from autistic patients, further implicating SEMA5A as an autism susceptibility gene. The linkage regions reported here provide targets for rare variation screening whereas the discovery of a single novel association demonstrates the action of common variants.

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