An X chromosome-wide association study in autism families identifies TBL1X as a novel autism spectrum disorder candidate gene in males

Abstract

<p>Abstract</p> <p>Background</p> <p>Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder with a strong genetic component. The skewed prevalence toward males and evidence suggestive of linkage to the X chromosome in some studies suggest the presence of X-linked susceptibility genes in people with ASD.</p> <p>Methods</p> <p>We analyzed genome-wide association study (GWAS) data on the X chromosome in three independent autism GWAS data sets: two family data sets and one case-control data set. We performed meta- and joint analyses on the combined family and case-control data sets. In addition to the meta- and joint analyses, we performed replication analysis by using the two family data sets as a discovery data set and the case-control data set as a validation data set.</p> <p>Results</p> <p>One SNP, rs17321050, in the transducin β-like 1X-linked (<it>TBL1X</it>) gene [OMIM:300196] showed chromosome-wide significance in the meta-analysis (<it>P </it>value = 4.86 × 10^-6) and joint analysis (<it>P </it>value = 4.53 × 10^-6) in males. The SNP was also close to the replication threshold of 0.0025 in the discovery data set (<it>P </it>= 5.89 × 10^-3) and passed the replication threshold in the validation data set (<it>P </it>= 2.56 × 10^-4). Two other SNPs in the same gene in linkage disequilibrium with rs17321050 also showed significance close to the chromosome-wide threshold in the meta-analysis.</p> <p>Conclusions</p> <p><it>TBL1X </it>is in the Wnt signaling pathway, which has previously been implicated as having a role in autism. Deletions in the Xp22.2 to Xp22.3 region containing <it>TBL1X </it>and surrounding genes are associated with several genetic syndromes that include intellectual disability and autistic features. Our results, based on meta-analysis, joint analysis and replication analysis, suggest that <it>TBL1X </it>may play a role in ASD risk.</p