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Candidate-gene screening and association analysis at the autism-susceptibility locus on chromosome 16p: evidence of association at GRIN2A and ABAT

BarnbyG, AbbottA, SykesN, MorrisA, WeeksD.E, MottR, Lamb J, BaileyA.J, MonacoA.P

Am. J. Hum. Genet. 2005;76(6):950-966.

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Abstract

Autism is a highly heritable neurodevelopmental disorder whose underlying genetic causes have yet to be identified. To date, there have been eight genome screens for autism, two of which identified a putative susceptibility locus on chromosome 16p. In the present study, 10 positional candidate genes that map to 16p11-13 were examined for coding variants: A2BP1, ABAT, BFAR, CREBBP, EMP2, GRIN2A, MRTF-B, SSTR5, TBX6, and UBN1. Screening of all coding and regulatory regions by denaturing high-performance liquid chromatography identified seven nonsynonymous changes. Five of these mutations were found to cosegregate with autism, but the mutations are not predicted to have deleterious effects on protein structure and are unlikely to represent significant etiological variants. Selected variants from candidate genes were genotyped in the entire International Molecular Genetics Study of Autism Consortium collection of 239 multiplex families and were tested for association with autism by use of the pedigree disequilibrium test. Additionally, genotype frequencies were compared between 239 unrelated affected individuals and 192 controls. Patterns of linkage disequilibrium were investigated, and the transmission of haplotypes across candidate genes was tested for association. Evidence of single-marker association was found for variants in ABAT, CREBBP, and GRIN2A. Within these genes, 12 single-nucleotide polymorphisms (SNPs) were subsequently genotyped in 91 autism trios (one affected individual and two unaffected parents), and the association was replicated within GRIN2A (Fisher's exact test, P<.0001). Logistic regression analysis of SNP data across GRIN2A and ABAT showed a trend toward haplotypic differences between cases and controls

Bibliographic metadata

Type of resource:
Content type:
Publication type:
Publication form:
Published date:
Journal title:
Volume:
76
Issue:
6
Start page:
950
End page:
966
Digital Object Identifier:
10.1086/430454
General notes:
  • DA - 20050506IS - 0002-9297 (Print)LA - engPT - Journal ArticlePT - Research Support, N.I.H., ExtramuralPT - Research Support, Non-U.S. Gov'tPT - Research Support, U.S. Gov't, P.H.SRN - 0 (Genetic Markers)RN - 0 (N-methyl D-aspartate receptor subtype 2A)RN - 0 (Protein Subunits)RN - 0 (Receptors, N-Methyl-D-Aspartate)RN - EC 2.6.1.19 (4-Aminobutyrate Transaminase)SB - IM
Access state:
Active

Record metadata

Manchester eScholar ID:
uk-ac-man-scw:1d17681
Created:
30th August, 2009, 14:30:07
Last modified by:
Lamb, Janine
Last modified:
17th November, 2012, 18:31:08

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