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Nature. 2009 Oct 8;461(7265):802-8. doi: 10.1038/nature08490.

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

Collaborators (195)

Arking DE, Brune CW, West K, O'Connor A, Hilton G, Tomlinson RL, West AB, Cook EH Jr, Chakravarti A, Weiss LA, Green T, Chang SC, Gabriel S, Gates C, Hanson EM, Kirby A, Korn J, Kuruvilla F, McCarroll S, Morrow EM, Neale B, Purcell S, Sasanfar R, Sougnez C, Stevens C, Altshuler D, Gusella J, Santangelo SL, Sklar P, Tanzi R, Daly MJ, Anney R, Bailey AJ, Baird G, Battaglia A, Berney T, Betancur C, Bölte S, Bolton PF, Brian J, Bryson SE, Buxbaum JD, Cabrito I, Cai G, Cantor RM, Cook EH Jr, Coon H, Conroy J, Correia C, Corsello C, Crawford EL, Cuccaro ML, Dawson G, de Jonge M, Devlin B, Duketis E, Ennis S, Estes A, Farrar P, Fombonne E, Freitag CM, Gallagher L, Geschwind DH, Gilbert J, Gill M, Gillberg C, Goldberg J, Green A, Green J, Guter SJ, Haines JL, Hallmayer JF, Hus V, Klauck SM, Korvatska O, Lamb JA, Laskawiec M, Leboyer M, Couteur AL, Leventhal BL, Liu XQ, Lord C, Lotspeich LJ, Maestrini E, Magalhaes T, Mahoney W, Mantoulan C, McConachie H, McDougle CJ, McMahon WM, Marshall CR, Miller J, Minshew NJ, Monaco AP, Munson J, Nurnberger JI Jr, Oliveira G, Pagnamenta A, Papanikolaou K, Parr JR, Paterson AD, Pericak-Vance MA, Pickles A, Pinto D, Piven J, Posey DJ, Poustka A, Poustka F, Regan R, Reichert J, Renshaw K, Roberts W, Roge B, Rutter ML, Salt J, Schellenberg GD, Scherer SW, Sheffield V, Sutcliffe JS, Szatmari P, Tansey K, Thompson AP, Tsiantis J, Van Engeland H, Vicente AM, Vieland VJ, Volkmar F, Wallace S, Wassink TH, Wijsman EM, Wing K, Wittemeyer K, Yaspan BL, Zwaigenbaum L, Morrow EM, Yoo SY, Hill RS, Mukaddes NM, Balkhy S, Gascon G, Al-Saad S, Hashmi A, Ware J, Joseph RM, LeClair E, Partlow JN, Barry B, Walsh CA, Pauls D, Moilanen I, Ebeling H, Mattila ML, Kuusikko S, Jussila K, Ignatius J, Sasanfar R, Tolouei A, Ghadami M, Rostami M, Hosseinipour A, Valujerdi M, Santangelo SL, Andresen K, Winkloski B, Haddad S, Kunkel L, Kohane Z, Tran T, Kong SW, O'Neil SB, Hanson EM, Hundley R, Holm I, Peters H, Baroni E, Cangialose A, Jackson L, Albers L, Becker R, Bridgemohan C, Friedman S, Munir K, Nazir R, Palfrey J, Schonwald A, Simmons E, Rappaport LA, Gauthier J, Mottron L, Joober R, Fombonne E, Rouleau G, Rehnstrom K, von Wendt L, Peltonen L.

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Center for Human Genetic Research, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA.


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.

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