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

Shweta Ramdas, Jonathan Judd, Sarah E Graham, Stavroula Kanoni, Yuxuan Wang, Ida Surakka, Brandon Wenz, Million Veterans Program, Shoa L Clarke, Alessandra Chesi, Andrew Wells, Konain Fatima Bhatti, Sailaja Vedantam, Thomas W Winkler, Adam E Locke, Eirini Marouli, Greg J M Zajac, Kuan-Han H Wu, Ioanna Ntalla, Qin HuiDerek Klarin, Austin T Hilliard, Zeyuan Wang, Chao Xue, Gudmar Thorleifsson, Anna Helgadottir, Daniel F Gudbjartsson, Hilma Holm, Isleifur Olafsson, Mi Yeong Hwang, Sohee Han, Masato Akiyama, Wei Zhao, Jing-Hua Zhao, Phuong Le, Niek Verweij, Jan W Benjamins, Ya Xing Wang, Peter J van der Most, Sander W van der Laan, Jun-Sing Wang, Folkert W Asselbergs, Albertine J Oldehinkel, Harold Snieder, Brenda Penninx, Meena Kumari, Pim van der Harst, Wei Huang, Young Jin Kim, Paul S de Vries, Xiang Zhu

Research output: Contribution to journalArticleAcademicpeer-review

14 Citations (Scopus)
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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.

Original languageEnglish
Pages (from-to)1366-1387
Number of pages22
JournalAmerican Journal of Human Genetics
Issue number8
Publication statusPublished - 4-Aug-2022


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