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

Ren-Hua Chung1, Deqiong Ma1, Kai Wang2, Dale J Hedges1, James M Jaworski1, John R Gilbert1, Michael L Cuccaro1, Harry H Wright3, Ruth K Abramson3, Ioanna Konidari1, Patrice L Whitehead1, Gerard D Schellenberg4, Hakon Hakonarson2, Jonathan L Haines5, Margaret A Pericak-Vance1 and Eden R Martin1*

Author Affiliations

1 Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, PO Box 019132 (M-860), Miami, FL 33101, USA

2 Center for Applied Genomics, Children's Hospital of Philadelphia, 34th St and Civic Center Blvd, Philadelphia, PA, 19104, USA

3 School of Medicine, University of South Carolina, 6311 Garners Ferry Road, Columbia, SC, 29209, USA

4 Department of Pathology and Laboratory Medicine, University of Pennsylvania, 3620 Hamilton Walk, Philadelphia, PA, USA

5 Center for Human Genetics Research, Vanderbilt University Medical Center, 2215 Garland Ave, Nashville, TN, 37232, USA

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Molecular Autism 2011, 2:18  doi:10.1186/2040-2392-2-18

Published: 4 November 2011



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.


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.


One SNP, rs17321050, in the transducin β-like 1X-linked (TBL1X) gene [OMIM:300196] showed chromosome-wide significance in the meta-analysis (P value = 4.86 × 10-6) and joint analysis (P value = 4.53 × 10-6) in males. The SNP was also close to the replication threshold of 0.0025 in the discovery data set (P = 5.89 × 10-3) and passed the replication threshold in the validation data set (P = 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.


TBL1X 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 TBL1X 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 TBL1X may play a role in ASD risk.