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

Million Veterans Program, Global Lipids Genetics Consortium, Shweta Ramdas, Jonathan Judd, Sarah E. Graham, Stavroula Kanoni, Yuxuan Wang, Ida Surakka, Brandon Wenz, 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 NtallaQin Hui, Derek 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, Saori Sakaue, Chikashi Terao, Masahiro Kanai, Wei Zhou, Ben M. Brumpton, Humaira Rasheed, Aki S. Havulinna, Yogasudha Veturi, Jennifer Allen Pacheco, Elisabeth A. Rosenthal, Nina Hutri-Kähönen, Leo Pekka Lyytikäinen, Kjell Nikus, Peter Kovacs, Mika Kähönen, Terho Lehtimäki, Jaakko Tuomilehto, Johanna Kuusisto, Shahid Abbas

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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
Issue number8
Publication statusPublished - 4 Aug 2022
Publication typeA1 Journal article-refereed


  • complex traits
  • fine-mapping
  • functional genomics
  • lipid biology
  • post-GWAS
  • regulatory mechanism
  • variant prioritization

Publication forum classification

  • Publication forum level 3

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)


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