The DLX1and DLX2 genes and susceptibility to autism spectrum disorders.
An imbalance between excitation and inhibition in the cerebral cortex has been suggested as a possible etiology of autism. The DLX genes encode homeodomain-containing transcription factors controlling the generation of GABAergic cortical interneurons. The DLX1 and DLX2 genes lie head-to-head in 2q32, a region associated with autism susceptibility. We investigated 6 Tag SNPs within the DLX1/2 genes in two cohorts of multiplex (MPX) and one of simplex (SPX) families for association with autism. Family-based association tests showed strong association with five of the SNPs. The common alleles of rs743605 and rs4519482 were significantly associated with autism (P<0.012) in the first sample of 138 MPX families, with the latter remaining significant after correction for multiple testing (P(cor)=0.0046). Findings in a second sample of 169 MPX families not only confirmed the association at rs4519482 (P=0.034) but also showed strong allelic association of the common alleles at rs788172, rs788173 and rs813720 (P(cor)=0.0003-0.04). In the combined MPX families, the common alleles were all significantly associated with autism (P(cor)=0.0005-0.016). The GGGTG haplotype was over transmitted in the two MPX cohorts and the combined samples [P(cor)<0.05: P(cor)=0.00007 for the combined MPX families, Odds Ratio: 1.75 (95% CI: 1.33-2.30)]. Further testing in 306 SPX families replicated the association at rs4519482 (P=0.033) and the over transmission of the haplotype GGGTG (P=0.012) although P-values were not significant after correction for multiple testing. The findings support the presence of two functional polymorphisms, one in or near each of the DLX genes that increase susceptibility to, or cause, autism in MPX families where there is a greater genetic component for these conditions.
Liu
Xudong
X
Department of Psychiatry, Queen's University, Kingston, Ontario, Canada.
Novosedlik
Natalia
N
Wang
Ami
A
Hudson
Melissa L
ML
Cohen
Ira L
IL
Chudley
Albert E
AE
Forster-Gibson
Cynthia J
CJ
Lewis
Suzanne M E
SM
Holden
Jeanette J A
JJ
D001321:Autistic Disorder / Q000235:genetics*; D015331:Cohort Studies; D005190:Family; D020022:Genetic Predisposition to Disease; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D020641:Polymorphism, Single Nucleotide; D014157:Transcription Factors / Q000235:genetics*
C088334:Distal-less homeobox proteins; D018398:Homeodomain Proteins; D014157:Transcription Factors