title: A genome-wide linkage and association scan reveals novel loci for autism.
abstract: 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.
authors.affiliation: Center for Human Genetic Research, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA.
authors.forename: Lauren A
authors.initials: LA
authors.lastname: Weiss
authors.forename: Dan E
authors.initials: DE
authors.lastname: Arking
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Daly
authors.forename: Aravinda
authors.initials: A
authors.lastname: Chakravarti
mesh_terms: D001321:Autistic Disorder / Q000235:genetics* / Q000378:metabolism; D001921:Brain / Q000378:metabolism; D002874:Chromosome Mapping; D002895:Chromosomes, Human, Pair 5 / Q000235:genetics; D008040:Genetic Linkage / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D055106:Genome-Wide Association Study; D006801:Humans; D038622:Internationality; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D018401:Sample Size; D039961:Semaphorins
chemical_list: D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; C491228:SEMA5A protein, human; D039961:Semaphorins