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A genome-wide linkage and association scan reveals novel loci for autism


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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Figure 1: Genome-wide linkage results.
Figure 2: SEMA5A expression in autism brains.


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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.

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Correspondence to Mark 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).

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