Induced Pluripotent Stem Cell Differentiation Provides an Approach for Functional Validation of GWAS Variants in Metabolic Disease

Genome-wide association studies (GWAS) have highlighted a large number of genetic variants with potential disease association, but functional analysis and validation remains a challenge. Here we describe an approach to functionally validate these variants through the differentiation of induced pluripotent stem cells (iPSCs) to study cellular pathophysiology. We collected peripheral blood cells from Framingham Heart Study participants and reprogrammed them to iPSCs. We then differentiated 68 iPSC lines into hepatocytes and adipocytes to investigate the effect of the 1p13 rs12740374 variant on cardiometabolic disease phenotypes via transcriptomics and metabolomic signatures. We observed a clear association between rs12740374 and lipid accumulation and gene expression changes in differentiated hepatocytes, in particular expression of SORT1, CELSR2 and PSRC1, consistent with previous analysis of this variant using other approaches. Initial investigation of additional SNPs also highlighted correlations with gene expression. Thus, iPSC-based population studies seem promising for further development as a tool for the functional validation of GWAS variants. Overall design: 68 Induced Pluripotent Stem Cell Lines derived from 34 Participants Differentiated into white adipocytes and hepatocyte like cells