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