Analysis of the Role of Non-coding Sequence Variation in the Etiology of Tourette Syndrome

Grant Type
Grant Year
Institution Location
Institution Organization Name
University of California
Investigators Name
Ramenskiy, Vasily, PhD

There is a growing body of evidence indicating that a significant fraction of phenotypically important DNA elements are located in the non-coding regions of the human genome. On the other hand, recent studies suggest that the coding variation alone has limited power to explain the phenotypic variability and complex disease etiology. Earlier linkage and association studies in large TS pedigrees have found evidence for the genome-wide significant linkage signal on chromosome 2 in the region that extends across the entire arm of the chromosome. The subsequent exome-wide and targeted re-sequencing of 115 individuals from the TSAICG pedigree collection discovered an extensive amount of genetic variation in pedigree members across the exome and targeted no-coding custom regions of chromosome 2. The established analysis methods (VAAST, PLINK, association tests from (Zhu, 2011), etc.) applied to the coding variation across the whole exome did not seem to produce any statistically significant results that can unequivocally point to specific genes and provide the explanation for the observed disease phenotypes. One of possible reasons for that may be in restriction of variants of interest to coding missense variants only. The ultimate goal of this project is to explain the linkage signal observed in TS large families on chromosome 2p by means of accounting for both coding and non-coding variation with potential regulatory function. This includes development of the pipeline for annotation of non-coding sequence variants and prediction of potentially functional regulatory variants. After selection of candidate genes and variants, the discovered top candidate variants will be genotyped in individuals from affected sib pair TS families with subsequent association tests based on potentially functional coding and non-coding variants, including their epistatic interactions. Vasily Ramenskiy, Ph.D., Giovanni Coppola, M.D., Nelson B. Freimer, M.D., and Jeremiah M. Scharf, M.D., Ph.D., University of California, Los Angeles, Los Angeles, CA Award: $150,000 Tourette Association of America Inc. – Research Grant Award 2014-2015