The DLX1and DLX2 Genes and Susceptibility to Autism Spectrum Disorders

Background: An imbalance between excitation and inhibition in the cortex has been suggested as a possible etiology of autism. The DLX genes encode homeobox transcription factors that have been implicated in the development of the GABAergic system. The DLX1 and DLX2 genes lie head-to- head in 2q32, a region associated with autism susceptibility.

Objectives:   To investigated the DLX1 and DLX2 genes in ASD families for association with susceptibility to autism

Methods: We genotyped 6 Tag SNPs covering the DLX1 and DLX2 genes in TEST and REPLICATION cohorts of Multiplex (MPX) familie and a group of Simplex (SPX) families as well as a control sample. We performed both family-based association and population-based case-control analyses. 

Results: Family-based association tests showed strong association with 5 of the 6 SNPs. The common alleles of rs743605 and rs4519482 were significantly associated with autism (P<0.012) in a TEST sample of 138 MPX families. Testing in a REPLICATION 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 (all P<0.01).  In the combined sample of 307 MPX families, the common alleles were all significantly associated with autism (P< 0.01). Haplotype analysis identified a common risk allele containing GGGTG haplotype that was significantly over-transmitted in the two MPX cohorts and the combined samples (P<0.01). Further testing in 306 Simplex families replicated only the association at rs4519482 (P =0.033) in single SNP analysis and the over-transmission of the GGGTG haplotype (P=0.012) with the significance being lower than that in the MPX families.

Conclusions: The results suggest that genetic variants in the DLX1/DLX2 genes may affect susceptibility or cause autism in families where there is a genetic loading for these conditions.