Abstract

Autism spectrum disorders (ASDs) are common, heritable neurodevelopmental conditions. The genetic architecture of ASDs is complex, requiring large samples to overcome heterogeneity. Here we broaden coverage and sample size relative to other studies of ASDs by using Affymetrix 10K SNP arrays and 1,181 families with at least two affected individuals, performing the largest linkage scan to date while also analyzing copy number variation in these families. Linkage and copy number variation analyses implicate chromosome 11p12–p13 and neurexins, respectively, among other candidate loci. Neurexins team with previously implicated neuroligins for glutamatergic synaptogenesis, highlighting glutamate-related genes as promising candidates for contributing to ASDs.

1. Department of Psychiatry and Behavioural Neurosciences, McMaster University, Hamilton, Ontario L8N 3Z5, Canada.
2. The Centre for Applied Genomics and Program in Genetics and Genome Biology, The Hospital for Sick Children and University of Toronto, Toronto, Ontario M5G 1X8, Canada.
3. Department of Pediatrics, McMaster University, Hamilton, Ontario L8N 3Z5 Canada.
4. Autism Research Unit, The Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada.
5. Centre for Addiction and Mental Health, Clarke Institute and Department of Psychiatry, University of Toronto, Toronto, Ontario M5G 1X8, Canada.
6. Departments of Pediatrics and Psychology, Izaak Walton Killam Health Centre – Dalhousie University, Halifax, Nova Scotia B3K 6R8, Canada.
7. Department of Neural and Behavioral Sciences, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033, USA.
8. Columbus Children's Research Institute, Center for Quantitative and Computational Biology, Columbus, Ohio 43205 USA.
9. University of Iowa, Department of Computer Science, Iowa City, Iowa 52242, USA.
10. Miami Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, Florida 33101, USA.
11. W.S. Hall Psychiatric Institute, University of South Carolina, Columbia, South Carolina 29208, USA.
12. INSERM U513, Université Paris XII, Créteil 94000, France.
13. Human Genetics and Cognitive Functions, Institut Pasteur, Paris 75015, France.
14. Department of Child and Adolescent Psychiatry, Goteborg University, Goteborg 41119, Sweden.
15. Department of Psychiatry, Groupe hospitalier Henri Mondor-Albert Chenevier, AP-HP, Créteil 94000, France.
16. Seaver Autism Research Center and the Greater New York Autism Research Center for Excellence, Department of Psychiatry, Mount Sinai School of Medicine, New York, New York 10029, USA.
17. Stanford University, Department of Psychiatry, Stanford, California 94304, USA.
18. Center for Molecular Neuroscience, Vanderbilt University, Nashville, Tennessee 37232, USA.
19. Center for Human Genetics Research, Vanderbilt University, Nashville 37232, Tennessee, USA.
20. Department of Psychiatry, Johns Hopkins University, Baltimore, Maryland 21287, USA.
21. University of North Carolina, Chapel Hill, North Carolina 27599, USA.
22. University of Iowa, Iowa City, Iowa 52242, USA.
23. Department of Neurology, University of California - Los Angeles (UCLA) School of Medicine, Los Angeles, California 90095, USA.
24. University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
25. New York State Institute for Basic Research in Developmental Disabilities, Staten Island, New York 10314, USA.
26. Department of Human Genetics, UCLA School of Medicine, Los Angeles, California 90095, USA.
27. Washington University School of Medicine, St. Louis, Missouri, USA.
28. University of Chicago, Chicago 60637, Illinois, USA.
29. Harvard Medical School, Boston, Massachusetts 02115, USA.
30. Cure Autism Now, Los Angeles, California 90036, USA.
31. Emory University, Atlanta, Georgia 30322, USA.
32. George Washington University, Washington, D.C. 20052, USA.
33. UCLA, Los Angeles, California 90095, USA.
34. Yale University Child Study Center, New Haven, Connecticut 06520, USA.
35. Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
36. Department of Psychiatry, University of Utah, Salt Lake City 84132, USA.
37. Department of Psychology and the Center on Human Development and Disability, University of Washington, Seattle, Washington 98195, USA.
38. Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, Washington 98195, USA.
39. Department of Psychiatry, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA.
40. Department of Pediatrics, University of California, Irvine, California 92697, USA.
41. Geriatrics Research Education and Clinical Center, Puget Sound Veterans Affairs Medical Center, Seattle, Washington 98108, USA.
42. Gerontology and Geriatric Medicine, Department of Medicine, University of Washington, Seattle, Washington 98104, USA.
43. Department of OB/GYN, University of Rochester Medical Center, Rochester, New York 14642, USA.
44. Departments of Neurology and Pharmacology, University of Washington, Seattle, Washington 98195, USA.
45. Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, Washington 98195, USA.
46. Department of Biostatistics, University of Washington, Seattle, Washington 98195, USA.
47. Université de Toulouse Le Mirail, Centre d'Etudes et de Recherches en Psychopathologie (CERPP), 31058 Toulouse, France.
48. Deutsches Krebsforschungszentrum (DKFZ), Division of Molecular Genome Analysis, D-69120 Heidelberg, Germany.
49. J W Goethe Universität Frankfurt, Klinik für Psychiatrie und Psychotherapie des Kindes- und Jugendalters, D-60528 Frankfurt, Germany.
50. National and Kapodistrian University of Athens, Department of Child Psychiatry, "Agia Sophia" Children's Hospital, Athens 115 27, Greece.
51. Department of Biology, University of Bologna, 40126 Bologna, Italy.
52. University Medical Center, Utrecht, Department of Child and Adolescent Psychiatry, 3508 GA Utrecht, The Netherlands.
53. Guy's Hospital, Newcomen Centre, London SE1 9RT, UK.
54. Institute of Psychiatry, Department of Child and Adolescent Psychiatry, London, UK.
55. Institute of Psychiatry, Social, Genetic and Developmental Psychiatry Centre (SGDP), London SE5 8AF, UK.
56. University of Cambridge Clinical School, Cambridge CB2 2AH, UK.
57. University of Manchester Department of Child Psychiatry, Booth Hall Children's Hospital, Manchester M9 7AA, UK.
58. University of Manchester School of Epidemiology and Health Science, Manchester M13 9P, UK.
59. University of Newcastle, Child and Adolescent Mental Health, Sir James Spence Institute, Newcastle upon Tyne NE1 4LP, UK.
60. University of Oxford Department of Psychiatry, Oxford OX3 7LQ, UK.
61. Wellcome Trust Centre for Human Genetics, Oxford OX3 7BN, UK.
62. Institute for Juvenile Research, Department of Psychiatry, University of Illinois at Chicago, Chicago, Illinois, 60608, USA.
63. University of Michigan Autism and Communicative Disorders Center (UMACC), Ann Arbor, Michigan, 48109, USA.
64. University of Pittsburgh Department of Human Genetics, Pittsburgh, Pennsylvania 15213, USA.
65. Service de pédiatrie et génétique médicale, CHU de Toulouse, Toulouse, France.
66. Montreal Children's Hospital, McGill University, Montreal, Canada.
67. Autism Speaks, 2 Park Avenue, New York, New York 10016, USA.
68. These authors contributed equally to this work.

Correspondence to: Bernie Devlin^39,68 e-mail: devlinbj@upmc.edu

Correspondence to: Stephen W Scherer^2,68 e-mail: swscherer@sickkids.ca

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