1. ¹Department of Psychiatry, Queen's University, Kingston, Ontario, Canada
2. ²Autism Research Program, Ongwanada, Kingston, Ontario, Canada
3. ³ASD-CARC, Kingston, Ontario, Canada
4. ⁴Department of Psychology, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, NY, USA
5. ⁵Department of Pediatrics and Child Health, Children's Hospital, University of Manitoba, Winnipeg, Manitoba, Canada
6. ⁶Department of Family Medicine, Queen's University, Kingston, Ontario, Canada
7. ⁷Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada
8. ⁸Department of Physiology, Queen's University, Kingston, Ontario, Canada

Correspondence: Dr JJA Holden, Department of Psychiatry & Physiology, Queen's University, Autism Research Program, Ongwanada Resource Centre, 191 Portsmouth Avenue, Kingston, Ontario, Canada K7 M 8A6. Tel: +1 613 548 4417 ext.1165; Fax: +1 613 548 8385; E-mail: holdenj@post.queensu.ca

Received 5 March 2008; Revised 15 July 2008; Accepted 16 July 2008; Published online 27 August 2008.

Abstract

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.