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

2009; Nature Portfolio; Volume: 461; Issue: 7265 Linguagem: Inglês

10.1038/nature08490

1476-4687

Lauren A. Weiss, Dan E. Arking, Mark J. Daly, Aravinda Chakravarti, Camille W. Brune, Kristen M. West, Ashley O’Connor, Gina M. Hilton, R Tomlinson, Andrew B. West, Edwin H. Cook, Todd Green, Shun-Chiao Chang, Stacey B. Gabriel, Casey Gates, Ellen Hanson, Andrew Kirby, Joshua M. Korn, Finny G. Kuruvilla, Steven McCarroll, Eric M. Morrow, Benjamin M. Neale, Shaun Purcell, Roksana Sasanfar, Carrie Sougnez, Christine Stevens, David Altshuler, James F. Gusella, Susan L. Santangelo, Pamela Sklar, Rudolph E. Tanzi, Richard Anney, Anthony Bailey, Gillian Baird, Agatino Battaglia, T. P. Berney, Catalina Betancur, Sven Bölte, Patrick Bolton, Jessica Brian, Susan E. Bryson, Joseph D. Buxbaum, Ines Cabrito, Guiqing Cai, Rita M. Cantor, Hilary Coon, Judith Conroy, Catarina Correia, Christina Corsello, Emily L. Crawford, Michael L. Cuccaro, Géraldine Dawson, Maretha Jonge, Bernie Devlin, Eftichia Duketis, Sean Ennis, Annette Estes, Penny Farrar, Éric Fombonne, Christine M. Freitag, Louise Gallagher, Daniel H. Geschwind, John R. Gilbert, Michael Gill, Christopher Gillberg, Jeremy Goldberg, Andrew Green, Jonathan Green, Stephen J. Guter, Jonathan L. Haines, Joachim Hallmayer, Vanessa Hus, Sabine M. Klauck, Olena Korvatska, Janine A. Lamb, Magdalena Laskawiec, Marion Leboyer, Ann Le Couteur, Bennett L. Leventha, Xiaoqing Liu, Catherine Lord, Linda Lotspeich, Elena Maestrini, Tiago R. Magalhães, William J. Mahoney, Carine Mantoulan, Helen McConachie, Christopher J. McDougle, William M. McMahon, Christian R. Marshall, Judith Miller, Nancy J. Minshew, Anthony P. Monaco, Jeff Munson, John I. Nürnberger, Guiomar Oliveira, Alistair T. Pagnamenta, Katerina Papanikolaou, Jeremy Parr, Andrew D. Paterson, Margaret A. Pericak‐Vance, Andrew Pickles, Dalila Pinto, Joseph Piven, David J. Posey, Annemarie Poustka, Fritz Poustka, Regina Regan, Jennifer Reichert, Katy Renshaw, Wendy Roberts, Bernadette Rogé, Michael Rutter, Jeff Salt, Daniela Berg, Stephen W. Scherer, Val C. Sheffield, James S. Sutcliffe, Peter Szatmari, Katherine E. Tansey, Ann Thompson, John Tsiantis, Hermán van Engeland, Astrid M. Vicente, Veronica J. Vieland, Fred Volkmar, Simon Wallace, Thomas H. Wassink, Ellen M. Wijsman, Kirsty Wing, Kerstin Wittemeyer, Brian L. Yaspan, Lonnie Zwaigenbaum, Seung Yun Yoo, Robert Hill, Nahit Motavallı Mukaddes, Soher Balkhy, Generoso G. Gascon, Samira Al-Saad, Asif Hashmi, Janice Ware, Robert M. Joseph, Elaine LeClair, Jennifer N. Partlow, Brenda J. Barry, Christopher A. Walsh, David Pauls, Irma Moilanen, Hanna Ebeling, Marja Leena Mattila, Sanna Kuusikko, Katja Jussila, Jaakko Ignatius, Ala Tolouei, Majid Ghadami, Maryam Rostami, Azam Hosseinipour, Maryam Valujerdi, Kara Andresen, Brian Winkloski, Stephen A. Haddad, Lou Kunkel, Zak Kohane, Tram Bao Tran, Sek Won Kong, Stephanie Brewster O'Neil, Rachel J. Hundley, Ingrid A. Holm, Heather Peters, Elizabeth Baroni, Aislyn Cangialose, Lindsay Jackson, Lisa Albers, Ronald E. Becker, Carolyn Bridgemohan, Sandra Friedman, Kerim Münir, Ramzi Nazir, Judith S. Palfrey, Alison Schonwald, Esau Simmons, Leonard Rappaport, Julie Gauthier, Laurent Mottron, Ridha Joober, Guy A. Rouleau, Karola Rehnström, Lennart von Wendt, Leena Peltonen,

Genetics and Neurodevelopmental Disorders

Although autism is a highly heritable neurodevelopmental disorder, attempts to identify specific susceptibility genes have thus far met with limited success. 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 x 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.