TY - JOUR
T1 - A multi-layer functional genomic analysis to understand noncoding genetic variation in lipids
AU - Million Veterans Program
AU - Global Lipids Genetics Consortium
AU - Ramdas, Shweta
AU - Judd, Jonathan
AU - Graham, Sarah E.
AU - Kanoni, Stavroula
AU - Wang, Yuxuan
AU - Surakka, Ida
AU - Wenz, Brandon
AU - Clarke, Shoa L.
AU - Chesi, Alessandra
AU - Wells, Andrew
AU - Bhatti, Konain Fatima
AU - Vedantam, Sailaja
AU - Winkler, Thomas W.
AU - Locke, Adam E.
AU - Marouli, Eirini
AU - Zajac, Greg J.M.
AU - Wu, Kuan Han H.
AU - Ntalla, Ioanna
AU - Hui, Qin
AU - Klarin, Derek
AU - Hilliard, Austin T.
AU - Wang, Zeyuan
AU - Xue, Chao
AU - Thorleifsson, Gudmar
AU - Helgadottir, Anna
AU - Gudbjartsson, Daniel F.
AU - Holm, Hilma
AU - Olafsson, Isleifur
AU - Hwang, Mi Yeong
AU - Han, Sohee
AU - Akiyama, Masato
AU - Sakaue, Saori
AU - Terao, Chikashi
AU - Kanai, Masahiro
AU - Zhou, Wei
AU - Brumpton, Ben M.
AU - Rasheed, Humaira
AU - Havulinna, Aki S.
AU - Veturi, Yogasudha
AU - Pacheco, Jennifer Allen
AU - Rosenthal, Elisabeth A.
AU - Lingren, Todd
AU - Feng, Qi Ping
AU - Kullo, Iftikhar J.
AU - Narita, Akira
AU - Takayama, Jun
AU - Martin, Hilary C.
AU - Hunt, Karen A.
AU - Trivedi, Bhavi
AU - Zhu, Xiang
N1 - Publisher Copyright:
© 2022 American Society of Human Genetics
PY - 2022/8/4
Y1 - 2022/8/4
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85135598739&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85135598739&partnerID=8YFLogxK
U2 - 10.1016/j.ajhg.2022.06.012
DO - 10.1016/j.ajhg.2022.06.012
M3 - Article
C2 - 35931049
AN - SCOPUS:85135598739
SN - 0002-9297
VL - 109
SP - 1366
EP - 1387
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
IS - 8
ER -