1. Center for Applied Genomics, Children's Hospital of Philadelphia, Pennsylvania 19104, USA
2. The Miami Institute for Human Genomics and Department of Human Genetics, University of Miami, Miami, Florida 33101, USA
3. Department of Genetics, University of Pennsylvania, Philadelphia, Pennsylvania 19014, USA
4. Department of Neurology and Center for Autism Research and Treatment, University of California Los Angeles, Los Angeles, California 90095, USA
5. Seaver Autism Center for Research and Treatment, Department of Psychiatry, Mount Sinai School of Medicine, New York, New York 10029, USA
6. Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19014, USA
7. Department of Biomedical Engineering, University of Southern California and Autism Speaks, Los Angeles, California 90089, USA
8. Department of Psychiatry, University of Washington, Seattle, Washington 98105, USA
9. Department of Psychiatry, University of North Carolina and Carolina Institute for Developmental Disabilities, Chapel Hill, North Carolina 27599, USA
10. The M.I.N.D. Institute and Department of Psychiatry and Behavioral Sciences, University of California Davis, Sacramento, California 95817, USA
11. Department of Genetics and Child Study Center, Yale University, New Haven, Connecticut 06520, USA
12. Institute for Juvenile Research and Department of Psychiatry, University of Illinois at Chicago, Chicago, Illinois 60608, USA
13. Department of Human Genetics, University of California Los Angeles, Los Angeles, California 90095, USA
14. Department of Psychiatry, University of Utah, Salt Lake City, Utah 84132, USA
15. Department of Psychiatry, University of Iowa, Iowa City, Iowa 84112, USA
16. Institute of Psychiatric Research, Indiana University, Indianapolis, Indiana 46202, USA
17. Center for Human Genetics Research, Vanderbilt University, Nashville, Tennessee 37232, USA
18. Center for Molecular Neuroscience and Vanderbilt Kennedy Center, Vanderbilt University, Nashville, Tennessee 37232, USA
19. Departments of Psychiatry and Neurology, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, USA
20. Departments of Psychiatry, Neuroscience, and Genetics and Genomic Sciences, Mount Sinai School of Medicine, New York, New York 10029, USA
21. Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19014, USA
22. These authors contributed equally to this work.

Correspondence to: Hakon Hakonarson^1,6 Correspondence and requests for materials should be addressed to H.H. (Email: hakonarson@chop.edu).

Abstract

Autism spectrum disorders (ASDs) represent a group of childhood neurodevelopmental and neuropsychiatric disorders characterized by deficits in verbal communication, impairment of social interaction, and restricted and repetitive patterns of interests and behaviour. To identify common genetic risk factors underlying ASDs, here we present the results of genome-wide association studies on a cohort of 780 families (3,101 subjects) with affected children, and a second cohort of 1,204 affected subjects and 6,491 control subjects, all of whom were of European ancestry. Six single nucleotide polymorphisms between cadherin 10 (CDH10) and cadherin 9 (CDH9)—two genes encoding neuronal cell-adhesion molecules—revealed strong association signals, with the most significant SNP being rs4307059 (P = 3.4  10^-8, odds ratio = 1.19). These signals were replicated in two independent cohorts, with combined P values ranging from 7.4  10^-8 to 2.1  10^-10. Our results implicate neuronal cell-adhesion molecules in the pathogenesis of ASDs, and represent, to our knowledge, the first demonstration of genome-wide significant association of common variants with susceptibility to ASDs.

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