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

Chung RH, Ma D, Wang K, Hedges DJ, Jaworski JM, Gilbert JR, Cuccaro ML, Wright HH, Abramson RK, Konidari I, Whitehead PL, Schellenberg GD, Hakonarson H, Haines JL, Pericak-Vance MA, Martin ER.

Abstract

ABSTRACT:

BACKGROUND:

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder with a strong genetic component. The skewed prevalence toward males compared to females and evidence of suggestive linkage to the X chromosome in some studies suggest the presence of X-linked susceptibility genes for ASD.

METHODS:

We analyzed genome-wide association study (GWAS) data on the X chromosome in three independent autism GWAS datasets: two family datasets and one case-control dataset. We performed meta- and joint analyses on the combined family and case-control datasets. In addition to the meta- and joint analyses, we performed replication analysis by using the two family datasets as a discovery dataset and the case-control dataset as a validation dataset.

RESULTS:

One SNP rs17321050 in the TBL1X (transducin (beta)-like 1X-linked, OMIM: 300196) gene showed chromosome-wide significance in the meta-analysis (p-value=4.86x10E-6) and joint analysis (p-value=4.53x10E-6) in males. The SNP was also close to the replication threshold of 0.0025 in the discovery dataset (p=5.89x10E-3) and passed the replication threshold in the validation (p=2.56x10E-4) dataset. Two other SNPs in the same gene in LD linkage disequilibrium (LD) with rs17321050 also showed significance close to the chromosome-wide threshold in the meta-analysis.

CONCLUSIONS:

TBL1X is in the Wnt signaling pathway, which has previously been implicated in autism. Deletions in the Xp22.2-Xp22.3 region containing TBL1X and surrounding genes are associated with several genetic syndromes that include intellectual disability and autistic features. Our results, through both meta- and joint and replication analyses, suggest that TBL1X may play a role in ASD risk.