Although autism is a highly heritable neurodevelopmental disorder, attempts to identify specific susceptibility genes have thus far met with limited success 1. Genome-wide association studies (GWAS) 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 (http://www.genome.gov/26525384). Consequently, we initiated a linkage and association mapping study using half a million genome-wide 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 a 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 while the discovery of a single novel association demonstrates the action of common variants. ; PUBLISHED ; 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 EDSP family sample was provided by the NLM Family foundation. Support for the MGH-Finnish collaborative sample was provided by NARSAD. Support for the HMCA came from NIMH (1R01 MH083565), the Nancy Lurie Marks (NLM) Family Foundation, the Simons Foundation. E.M.M. 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. L.A.W. was supported by a Ruth L. Kirschstein National Research Service Award. 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), 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 Principal Investigators and Co-Investigators were: Stanford University, Stanford: Neil Risch, Ph.D., Richard M. Myers, Ph.D., Donna Spiker, Ph.D., Linda J. Lotspeich, M.D., Joachim Hallmayer, M.D., Helena C. Kraemer, Ph.D., Roland D. Ciaranello, M.D., Luigi Luca Cavalli-Sforza, M.D.; University of Utah, Salt Lake City: William M. McMahon, M.D. and P. Brent Petersen. 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 Principal Investigator is Daniel H. Geschwind, M.D., Ph.D. (UCLA). The Co-Principal Investigators include Stanley F. Nelson, M.D. and Rita Cantor, Ph.D. (UCLA), Christa Lese Martin, Ph.D. (U. Chicago), T. Conrad Gilliam, Ph.D (Columbia). Co-investigators include Maricela Alarcon Ph.D. (UCLA), Kenneth Lange, Ph.D. (UCLA), Sarah J. Spence M.D. Ph.D. (UCLA), David H. Ledbetter Ph.D. (Emory) and Hank Juo, M.D., Ph.D. (Columbia). Scientific oversight of the AGRE program is provided by a steering committee (Chair: Daniel H. Geschwind, M.D., Ph.D. Members: W. Ted Brown, M.D., Ph.D., Maja Bucan, Ph.D., Joseph Buxbaum, Ph.D., T. Conrad Gilliam, Ph.D., David Greenberg, Ph.D., David Ledbetter, Ph.D., Bruce Miller, M.D., Stanley F. Nelson, M.D., Jonathan Pevsner, Ph.D., Carol Sprouse, Ed.D., Gerard Schellenberg, Ph.D., Rudolph Tanzi, Ph.D. The AGP work was supported by the following grants: 1. The Hilibrand Foundation (Principal Investigator: Joachim 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).