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

Ramdas, S. ; Poveda, A. LU orcid ; Kurbasic, A. LU ; Lyssenko, V. LU ; Franks, P.W. LU and Brown, Christopher D. (2022) In American Journal of Human Genetics 109(8). p.1366-1387
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... (More)
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. © 2022 American Society of Human Genetics (Less)
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author
; ; ; ; and
author collaboration
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
complex traits, fine-mapping, functional genomics, lipid biology, post-GWAS, regulatory mechanism, variant prioritization, lipid, chromatin, genetics, genome-wide association study, genomics, human, single nucleotide polymorphism, Chromatin, Genome-Wide Association Study, Genomics, Humans, Lipids, Polymorphism, Single Nucleotide
in
American Journal of Human Genetics
volume
109
issue
8
pages
22 pages
publisher
Cell Press
external identifiers
  • scopus:85135598739
  • pmid:35931049
ISSN
0002-9297
DOI
10.1016/j.ajhg.2022.06.012
language
English
LU publication?
yes
id
18eea727-15e8-44ae-8089-2f683de2fa23
date added to LUP
2022-09-16 10:54:15
date last changed
2024-04-02 10:16:59
@article{18eea727-15e8-44ae-8089-2f683de2fa23,
  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. © 2022 American Society of Human Genetics}},
  author       = {{Ramdas, S. and Poveda, A. and Kurbasic, A. and Lyssenko, V. and Franks, P.W. and Brown, Christopher D.}},
  issn         = {{0002-9297}},
  keywords     = {{complex traits; fine-mapping; functional genomics; lipid biology; post-GWAS; regulatory mechanism; variant prioritization; lipid; chromatin; genetics; genome-wide association study; genomics; human; single nucleotide polymorphism; Chromatin; Genome-Wide Association Study; Genomics; Humans; Lipids; Polymorphism, Single Nucleotide}},
  language     = {{eng}},
  number       = {{8}},
  pages        = {{1366--1387}},
  publisher    = {{Cell Press}},
  series       = {{American Journal of Human Genetics}},
  title        = {{A multi-layer functional genomic analysis to understand noncoding genetic variation in lipids}},
  url          = {{http://dx.doi.org/10.1016/j.ajhg.2022.06.012}},
  doi          = {{10.1016/j.ajhg.2022.06.012}},
  volume       = {{109}},
  year         = {{2022}},
}