Journal Article

The DLX1and DLX2 genes and susceptibility to autism spectrum disorders

Lewis, Suzanne M E, Hudson, Melissa L, Chudley, Albert E, Novosedlik, Natalia, Holden, Jeanette J A, Wang, Ami, Liu, Xudong, Cohen, Ira L, Forster-Gibson, Cynthia J

2009

Overview

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.

• Publisher: Springer International Publishing,Nature Publishing Group
• Subject: Alleles / Autism / Autistic Disorder - genetics / Bioinformatics / Biological and medical sciences / Biomedical and Life Sciences / Biomedicine / Brain research / Child clinical studies / Chromosome 2 / Cohort Studies / Cortex / Cytogenetics / Developmental disorders / Epilepsy / Etiology / Family / Fundamental and applied biological sciences. Psychology / Gene Expression / General aspects. Genetic counseling / Genes / Genetic Predisposition to Disease / Genetics / Genetics of eukaryotes. Biological and molecular evolution / Haplotypes / Homeobox / Homeodomain Proteins - genetics / Human Genetics / Humans / Hypotheses / Infantile autism / Interneurons / Medical genetics / Medical sciences / Molecular and cellular biology / Mutation / Neurobiology / Physiology / Polymorphism, Single Nucleotide / Psychiatry / Psychology. Psychoanalysis. Psychiatry / Psychopathology. Psychiatry / Single-nucleotide polymorphism / Transcription factors / Transcription Factors - genetics / γ-Aminobutyric acid