65 - IDENTIFYING SUSCEPTIBILITY LOCI FOR TOURETTE'S SYNDROME IN A DENSELY AFFECTED PEDIGREE

Abstract

Background Tourette's Syndrome (TS) is a highly heritable neuropsychiatric disorder with complex patterns of genetic inheritance, and recent genetic findings highlight the role of numerous common variants each with subtle effects. The existence of Mendelian subtypes of TS (rare variants of very strong effects) has been postulated; particularly as such variants could prove to be more tractable for subsequent biological investigation. One way to evaluate this hypothesis is via the study of pedigrees densely affected with TS in which a genetic variant of strong effect inherited from a common ancestor may be more likely. With the advent of high-throughput technologies, we can now search densely affected pedigrees for specific variants that may contribute to risk for TS. Methods We have access to DNA from a remarkable six-generation British pedigree with an exceptional prevalence of TS and two co-heritable conditions: chronic mild tics (CMT) and Obsessive-Compulsive Disorder (OCD). This 122-member pedigree contains 35 cases with TS, 12 with CMT and 7 with OCD (DNA is available for 57 individuals: 25 TS, 9 CMT, 6 OCD, 17 unaffected). The lifetime prevalence of TS and related disorders in this large pedigree makes it a strong candidate for identifying genetic risk factors of near-Mendelian effects. Our ongoing search strategy is iterative and involves a combination of methodologies. First, we genotyped all 57 available DNA samples with a microarray (Illumina MEGA) providing information for 2.5 million single nucleotide polymorphisms (SNPs) to identify shared segments, runs of identity-by-state and copy number variants (CNVs). Second, a subset of the 10 most informative samples were whole genome sequenced at 30X coverage to identify putative causative mutations. Results Analyses for these first two steps are currently ongoing. Following their completion, we will focus on putatively causal mutations and genotype them in all 57 individuals with DNA available to examine patterns of inheritance. Finally, regardless of the outcome of these analyses, we will calculate Polygenic Risk Scores (PRS) for TS and OCD in all cases from this pedigree and compare them to matched controls. Discussion This will allow us to test an alternative hypothesis of whether this densely affected pedigree has more to do with common versus rare variants. Successful completion of this study has great potential to identify novel, highly penetrant mutations causing TS and related conditions, opening up a window into their pathophysiology.