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X-Chromosome Study Uncovers New Autism Risk Variant

By Andrea Anderson

NEW YORK (GenomeWeb News) – In a study online today in the journal Molecular Autism, researchers from the University of Miami and elsewhere reported on a new autism-associated variant that they detected in a Wnt signaling pathway gene through an association study focused exclusively on the X chromosome.

The team brought together data from three past genome-wide association studies — two studies based on data for individuals from autism-affected families and one case-control study — to look for genetic ties to autism on the X chromosome. After doing a few different types of analyses, the team found an association between autism and a variant in the transducin beta-like 1X-linked gene TBL1X.

"The gene is interesting because it is involved in the Wnt signaling pathway," the study's first author Ren-Hua Chung, director of the statistical genetics division at the University of Miami's John P. Hussman Institute for Human Genomics, told GenomeWeb Daily News. "Genes in that pathway have been found to be associated with autism before. But this specific gene, TBL1X, has not been reported to be associated with autism."

Moreover, he and his co-authors noted, past studies suggest that deletions in and around the TBL1X gene can contribute to syndromes that involve intellectual or developmental disability and/or some features that overlap with autism.

Because autism spectrum disorder, or ASD, is roughly four times as common in males as it is in females, some researchers have started scrutinizing the X chromosome for clues to the genetics of this neurodevelopmental condition.

"It has been known that males have a higher risk of developing autism than females," Chung said, noting that some linkage and copy number studies have implicated the X chromosome in autism. "So this motivated us to perform X chromosome-specific studies analyses for autism."

Although some studies have looked for associations on the X chromosome in the past, he added, most of the potential autism-associated signals reported on the sex chromosome so far have been subtle, owing to relatively small sample sizes.

"There have several studies done for the X chromosome, but the signal is not so strong, probably due to the limit of the sample size used," Chung explained. "So we decided to perform a large-scale study, which included thousands of samples, to try to increase the statistical power."

The researchers relied on three data sets for this X chromosome-based association study: two family-based sample sets, one assembled by investigators at the Hussman Institute for Human Genomics and their collaborators and another provided by the Autism Genetic Resource Exchange, and a case-control group enrolled for studies led by Children's Hospital of Philadelphia researchers.

Overall, the team analyzed data on 2,557 samples from 735 families affected by ASD from the first sample set and 3,289 individuals from another 721 ASD families. From the case-control they had data for1,204 individuals with ASD and 6,472 unaffected controls.

Individuals from one of the family-based cohorts were genotyped on the Illumina Infinium Human1M BeadChip array, while individuals from the other family cohort and case-control group were genotyped on the Illumina HumanHap550 BeadChip array.

Along with a joint analysis of data from all three cohorts, the team used raw genotyping information from the two family datasets for the discovery phase of an X chromosome association study that they subsequently validated using the case-control dataset. They also did a meta-analysis based on p-values from previous studies rather than raw genotyping data.

Results from each of these X chromosome analyses were quite consistent with one another, Chung noted, leading researchers to an autism-associated SNP in an intron of TBL1X, a gene that codes for a member of the Wnt signaling pathway. Additional variants in linkage disequilibrium with that SNP were also linked to ASD in the team's meta-analysis.

"The SNP in TBL1X is associated with an increase in risk for ASD of about 15 percent," senior author Eden Martin, also at the Hussman Institute for Human Genetics, said in a statement. "This could reflect either an unidentified rare mutation (or mutations), which has large impact, or a more common change with a more subtle effect, on the development of ASD."

Researchers plan to do fine mapping and targeted sequencing to try to determine whether there are any rare variants in the TBL1X region contributing to ASD risk, Chung said. They are also gearing up to analyze even larger sample sets to further enhance their statistical power for detecting ASD-associated variants on the X chromosome.

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