RU 2488, Project: Physiological relevance of genetic risk variants in reduced penetrance

To date, genome-wide association studies (GWAS) have identified thousands of loci associated with hundreds of complex diseases and traits. In more recent years, considerable progress has been made in elucidating the causal variants and genes underlying these associations. However, functional characterization of the mechanisms in GWAS loci is a complex challenge. These challenges include linkage disequilibrium and allelic heterogeneity at each locus, the non-coding nature of most loci, and the time and cost required to evaluate the potential mechanistic contributions of genes and variants experimentally. Furthermore, any signal within a locus can affect the same or different target genes. Identifying mechanisms responsible for GWAS loci requires an accumulation of consistent evidence for the genes and variants that influence the trait or disease in humans. Experimental studies on genes and variants may differ based on cell type, cell environment, or other context-specific variables. In P9 we will make use of established in silico as well as in vitro workflows to elucidate the physiological relevance of genetic variants in reduced penetrance of Parkinson’s disease (PD), dystonia, and X-linked dystonia-parkinsonism (XDP). As a starting point, we will use multiple candidate regions identified on nine chromosomes through the GWAS approach in the first funding period of ProtectMove (projects P5-P7). These will further be analyzed in a systematic, comprehensive, and organized fashion with the goal to create an efficient and standardized workflow that would provide an informative overview of findings and allow for recognition of ensuing patterns, and their overall relevance for reduced penetrance in hereditary movement disorders. Briefly, in Objective 1 we will perform in silico evaluation and prioritization of variants/regions identified in the GWASs mentioned above. In Objective 2 we will employ a variety of experimental strategies to elucidate the mechanisms and physiological relevance of the most compelling (and currently for the most part unknown), variants from Objective 1. Finally, in our Objective 3, we will modulate elements regulating the genes with disturbed (down or up-regulated) expression to compensate for the detected dosage effects. Thus, we aim not only to identify and functionally characterize the variants modifying penetrance and expressivity of PD, dystonia, and XDP, but also to devise means for boosting or ameliorating their effect.