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

Ren Hua Chung, Deqiong Ma, Kai Wang, Dale J. Hedges, James M. Jaworski, John Gilbert, Michael Cuccaro, Harry H. Wright, Ruth K. Abramson, Ioanna Konidari, Patrice L. Whitehead, Gerard D. Schellenberg, Hakon Hakonarson, Jonathan L. Haines, Margaret A Pericak-Vance, Eden R Martin

Research output: Contribution to journalArticle

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Abstract

Background: 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. Methods. 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. Results: One SNP, rs17321050, in the transducin -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. Conclusions: 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.

Original languageEnglish
Article number18
JournalMolecular Autism
Volume2
Issue number1
DOIs
StatePublished - Dec 1 2011

Fingerprint

X Chromosome
Autistic Disorder
Genes
Meta-Analysis
Single Nucleotide Polymorphism
Genome-Wide Association Study
Chromosomes
Joints
Autism Spectrum Disorder
Datasets
Transducin
Genetic Databases
X-Linked Genes
Wnt Signaling Pathway
Linkage Disequilibrium
Intellectual Disability

ASJC Scopus subject areas

  • Psychiatry and Mental health
  • Developmental Neuroscience
  • Developmental Biology
  • Molecular Biology

Cite this

An X chromosome-wide association study in autism families identifies TBL1X as a novel autism spectrum disorder candidate gene in males. / Chung, Ren Hua; Ma, Deqiong; Wang, Kai; Hedges, Dale J.; Jaworski, James M.; Gilbert, John; Cuccaro, Michael; Wright, Harry H.; Abramson, Ruth K.; Konidari, Ioanna; Whitehead, Patrice L.; Schellenberg, Gerard D.; Hakonarson, Hakon; Haines, Jonathan L.; Pericak-Vance, Margaret A; Martin, Eden R.

In: Molecular Autism, Vol. 2, No. 1, 18, 01.12.2011.

Research output: Contribution to journalArticle

Chung, RH, Ma, D, Wang, K, Hedges, DJ, Jaworski, JM, Gilbert, J, Cuccaro, M, Wright, HH, Abramson, RK, Konidari, I, Whitehead, PL, Schellenberg, GD, Hakonarson, H, Haines, JL, Pericak-Vance, MA & Martin, ER 2011, 'An X chromosome-wide association study in autism families identifies TBL1X as a novel autism spectrum disorder candidate gene in males', Molecular Autism, vol. 2, no. 1, 18. https://doi.org/10.1186/2040-2392-2-18
Chung, Ren Hua ; Ma, Deqiong ; Wang, Kai ; Hedges, Dale J. ; Jaworski, James M. ; Gilbert, John ; Cuccaro, Michael ; Wright, Harry H. ; Abramson, Ruth K. ; Konidari, Ioanna ; Whitehead, Patrice L. ; Schellenberg, Gerard D. ; Hakonarson, Hakon ; Haines, Jonathan L. ; Pericak-Vance, Margaret A ; Martin, Eden R. / An X chromosome-wide association study in autism families identifies TBL1X as a novel autism spectrum disorder candidate gene in males. In: Molecular Autism. 2011 ; Vol. 2, No. 1.
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abstract = "Background: 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. Methods. 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. Results: One SNP, rs17321050, in the transducin -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. Conclusions: 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.",
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AU - Chung, Ren Hua

AU - Ma, Deqiong

AU - Wang, Kai

AU - Hedges, Dale J.

AU - Jaworski, James M.

AU - Gilbert, John

AU - Cuccaro, Michael

AU - Wright, Harry H.

AU - Abramson, Ruth K.

AU - Konidari, Ioanna

AU - Whitehead, Patrice L.

AU - Schellenberg, Gerard D.

AU - Hakonarson, Hakon

AU - Haines, Jonathan L.

AU - Pericak-Vance, Margaret A

AU - Martin, Eden R

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N2 - Background: 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. Methods. 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. Results: One SNP, rs17321050, in the transducin -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. Conclusions: 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.

AB - Background: 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. Methods. 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. Results: One SNP, rs17321050, in the transducin -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. Conclusions: 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.

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