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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 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.

Pubmed ID: 19812673

Authors

  • Weiss LA
  • Arking DE
  • Gene Discovery Project of Johns Hopkins & the Autism Consortium
  • Daly MJ
  • Chakravarti A

Journal

Nature

Publication Data

October 8, 2009

Associated Grants

  • Agency: NIMH NIH HHS, Id: 1K23MH080954
  • Agency: NIMH NIH HHS, Id: 1R01 MH083565
  • Agency: Autism Speaks, Id: AS2042
  • Agency: Medical Research Council, Id: G0601030
  • Agency: NICHD NIH HHS, Id: HD055782
  • Agency: NIMH NIH HHS, Id: MH00219
  • Agency: NIMH NIH HHS, Id: MH00980
  • Agency: NIMH NIH HHS, Id: MH081754
  • Agency: NIMH NIH HHS, Id: MH39437
  • Agency: NIMH NIH HHS, Id: MH52708
  • Agency: NIMH NIH HHS, Id: MH55135
  • Agency: NIMH NIH HHS, Id: MH55284
  • Agency: NIMH NIH HHS, Id: MH60007
  • Agency: NIMH NIH HHS, Id: MH61009
  • Agency: NIMH NIH HHS, Id: MH64547
  • Agency: NINDS NIH HHS, Id: NS042165
  • Agency: NICHD NIH HHS, Id: P50 HD055748
  • Agency: NICHD NIH HHS, Id: P50 HD055782
  • Agency: NIMH NIH HHS, Id: R01 MH060007
  • Agency: NIMH NIH HHS, Id: R01 MH060007-04A1
  • Agency: NIMH NIH HHS, Id: R01 MH060007-05
  • Agency: NIMH NIH HHS, Id: R01 MH060007-06
  • Agency: NCRR NIH HHS, Id: U54 RR020278
  • Agency: Medical Research Council, Id:

Mesh Terms

  • Autistic Disorder
  • Brain
  • Chromosome Mapping
  • Chromosomes, Human, Pair 5
  • Genetic Linkage
  • Genetic Predisposition to Disease
  • Genome-Wide Association Study
  • Humans
  • Internationality
  • Membrane Proteins
  • Nerve Tissue Proteins
  • Polymorphism, Single Nucleotide
  • Sample Size