Faculty, Staff and Student Publications

Language

English

Publication Date

8-4-2022

Journal

American Journal of Human Genetics

DOI

10.1016/j.ajhg.2022.06.012

PMID

35931049

PMCID

PMC9388392 D

PubMedCentral® Posted Date

8-5-2022

PubMedCentral® Full Text Version

Post-print

Abstract

A major challenge of genome-wide association studies (GWASs) 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. We highlight two of the prioritized genes, CREBRF and RRBP1, which show convergent evidence across functional datasets supporting their roles in lipid biology.

Keywords

Chromatin, Genome-Wide Association Study, Genomics, Humans, Lipids, Polymorphism, Single Nucleotide, lipid biology, fine-mapping, functional genomics, post-GWAS, regulatory mechanism, complex traits, variant prioritization

Published Open-Access

yes

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