Genome-wide association studies (GWAS) have identified many disease-associated variants, yet mechanisms underlying these associations remain unclear. To understand obesity-associated variants, we gene Show more
Genome-wide association studies (GWAS) have identified many disease-associated variants, yet mechanisms underlying these associations remain unclear. To understand obesity-associated variants, we generate gene regulatory annotations in adipocytes and hypothalamic neurons across cellular differentiation stages. We then test variants in 97 obesity-associated loci using a massively parallel reporter assay and identify putatively causal variants that display cell type specific or cross-tissue enhancer-modulating properties. Integrating these variants with gene regulatory information suggests genes that underlie obesity GWAS associations. We also investigate a complex genomic interval on 16p11.2 where two independent loci exhibit megabase-range, cross-locus chromatin interactions. We demonstrate that variants within these two loci regulate a shared gene set. Together, our data support a model where GWAS loci contain variants that alter enhancer activity across tissues, potentially with temporally restricted effects, to impact the expression of multiple genes. This complex model has broad implications for ongoing efforts to understand GWAS. Show less
Founder populations are ideally suited for studies on the clinical effects of alleles that are rare in general populations but occur at higher frequencies in these isolated populations. Whole genome s Show more
Founder populations are ideally suited for studies on the clinical effects of alleles that are rare in general populations but occur at higher frequencies in these isolated populations. Whole genome sequencing in 98 Hutterites, a founder population of European descent, and subsequent imputation revealed 660,238 single nucleotide polymorphisms that are rare (<1%) or absent in European populations, but occur at frequencies >1% in the Hutterites. We examined the effects of these rare in European variants on plasma lipid levels in 828 Hutterites and applied a Bayesian hierarchical framework to prioritize potentially causal variants based on functional annotations. We identified two novel non-coding rare variants associated with LDL cholesterol (rs17242388 in LDLR) and HDL cholesterol (rs189679427 between GOT2 and APOOP5), and replicated previous associations of a splice variant in APOC3 (rs138326449) with triglycerides and HDL-C. All three variants are at well-replicated loci in GWAS but are independent from and have larger effect sizes than the known common variation in these regions. Candidate eQTL analyses in in LCLs in the Hutterites suggest that these rare non-coding variants are likely to mediate their effects on lipid traits by regulating gene expression. Show less