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

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MARC

Ramdas, S.Univ Penn, Perelman Sch Med, Dept Genet, Philadelphia, PA 19104 USA,University of Pennsylvania (author)

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

Article/chapterEnglish2022

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Elsevier BV,2022

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LIBRIS-ID:oai:gup.ub.gu.se/318991
https://gup.ub.gu.se/publication/318991URI
https://doi.org/10.1016/j.ajhg.2022.06.012DOI
https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-485348URI
https://lup.lub.lu.se/record/18eea727-15e8-44ae-8089-2f683de2fa23URI
http://kipublications.ki.se/Default.aspx?queryparsed=id:150690307URI

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Language:English

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SwePubSwePub

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Subject category:ref swepub-contenttype
Subject category:art swepub-publicationtype

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For complete list of authors see http://dx.doi.org/10.1016/j.ajhg.2022.06.012De fem första författarna delar förstaförfattarskapet.
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.

Subject headings and genre

NATURVETENSKAP Biologi Genetik hsv//swe
NATURAL SCIENCES Biological Sciences Genetics hsv//eng
MEDICIN OCH HÄLSOVETENSKAP Medicinska och farmaceutiska grundvetenskaper Medicinsk genetik hsv//swe
MEDICAL AND HEALTH SCIENCES Basic Medicine Medical Genetics hsv//eng
integrative analysis
wide association
3d genome
variants
cholesterol
annotation
obesity
common
loci
expression
Genetics & Heredity
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

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Zhang, J. F. (author)
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Ho, Y. L. (author)
Lynch, J. A. (author)
Tsao, P. S. (author)
Chang, K. M. (author)
Cho, K. (author)
O'Donnell, C. J. (author)
Gaziano, J. M. (author)
Wilson, P. (author)
Mohlke, K. L. (author)
Frayling, T. M. (author)
Hirschhorn, J. N. (author)
Kathiresan, S. (author)
Boehnke, M. (author)
Grant, S. (author)
Natarajan, P. (author)
Sun, Y. V. (author)
Morris, A. P. (author)
Deloukas, P. (author)
Peloso, G. (author)
Assimes, T. L. (author)
Willer, C. J. (author)
Zhu, X. (author)
Brown, C. D.Univ Penn, Perelman Sch Med, Dept Genet, Philadelphia, PA 19104 USA,University of Pennsylvania (author)
Univ Penn, Perelman Sch Med, Dept Genet, Philadelphia, PA 19104 USAUniversity of Pennsylvania (creator_code:org_t)
The Million Veteran Program
Global Lipids Genetics Consortium

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About the subject

NATURAL SCIENCES: NATURAL SCIENCES; and Biological Scien ...; and Genetics

MEDICAL AND HEALTH SCIENCES: MEDICAL AND HEAL ...; and Basic Medicine; and Medical Genetics

Articles in the publication: American Journal ...

By the university: University of Gothenburg; Uppsala University; Lund University; Karolinska Institutet

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