A multi-layer functional genomic analysis to understand noncoding genetic variation in lipids

Abstract

A major challenge of genome-wide association studies (GWAS) is to translate phenotypic associations into biological insights. Here, we integrate a large GWAS on blood lipids involving 1.6 million individuals from five ancestries with a wide array of functional genomic datasets to discover regulatory mechanisms underlying lipid associations. We first prioritize lipid-associated genes with expression quantitative trait locus (eQTL) colocalizations, and then add chromatin interaction data to narrow the search for functional genes. Polygenic enrichment analysis across 697 annotations from a host of tissues and cell types confirms the central role of the liver in lipid levels, and highlights the selective enrichment of adipose-specific chromatin marks in high-density lipoprotein cholesterol and triglycerides. Overlapping transcription factor (TF) binding sites with lipid-associated loci identifies TFs relevant in lipid biology. In addition, we present an integrative framework to prioritize causal variants at GWAS loci, producing a comprehensive list of candidate causal genes and variants with multiple layers of functional evidence. Two prioritized genes, CREBRF and RRBP1, show convergent evidence across functional datasets supporting their roles in lipid biology.

Systematic elucidation of genetic mechanisms underlying cholesterol uptake

“…ARID1A is a core epigenetic regulator whose loss in mouse liver leads to pleiotropic changes, including elevated cholesterol. 81 In addition, the GWAS signal at the RRBP1 locus can be localized to a single fine-mapped variant (rs2618566, PIP = 1.00) in a distal regulatory region that is a liver expression quantitative trait loci (eQTL) 82 ( Figure S7 C). Our exome rare variant analysis identifies significantly decreased LDL-C in carriers of rare ARID1A and RRBP1 coding variants ( Figure S7 E), and mouse RRBP1 knockdown has been shown to disrupt lipid homeostasis and lead to lower circulating LDL-C levels.…”

Genome-Wide Association Studies and fine-mapping of genomic loci for n-3 and n-6 Polyunsaturated Fatty Acids in Hispanic American and African American Cohorts

“…Chromatin Contact Analysis We queried chromatin accessibility and promoter contacts in human mesenchymal stem cells (hMSC) and Adipocytes differentiated in vitro from these (hMSC_Adipocytes), embryonic stem cell derived hypothalamic neurons (hESC Hypothalamic Neurons), induced pluripotent-dervived Heptocytes (IPS-Hepatocytes), Enteroids, and the hepatic carcinoma HepG2 cell line. [44][45][46][47][48][49] Details on Promoter Capture C and ATAC-seq library generation and analyses have been previously described. 44 Gene Co-expression Analysis.…”