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المؤلفRamdas, Shweta
المؤلفJudd, Jonathan
المؤلفGraham, Sarah E.
المؤلفKanoni, Stavroula
المؤلفWang, Yuxuan
المؤلفSurakka, Ida
المؤلفWenz, Brandon
المؤلفClarke, Shoa L.
المؤلفChesi, Alessandra
المؤلفWells, Andrew
المؤلفBhatti, Konain Fatima
المؤلفVedantam, Sailaja
المؤلفWinkler, Thomas W.
المؤلفLocke, Adam E.
المؤلفMarouli, Eirini
المؤلفZajac, Greg J.M.
المؤلفWu, Kuan Han H.
المؤلفNtalla, Ioanna
المؤلفHui, Qin
المؤلفKlarin, Derek
المؤلفHilliard, Austin T.
المؤلفWang, Zeyuan
المؤلفXue, Chao
المؤلفThorleifsson, Gudmar
المؤلفHelgadottir, Anna
المؤلفGudbjartsson, Daniel F.
المؤلفHolm, Hilma
المؤلفOlafsson, Isleifur
المؤلفHwang, Mi Yeong
المؤلفHan, Sohee
المؤلفAkiyama, Masato
المؤلفSakaue, Saori
المؤلفTerao, Chikashi
المؤلفKanai, Masahiro
المؤلفZhou, Wei
المؤلفBrumpton, Ben M.
المؤلفRasheed, Humaira
المؤلفHavulinna, Aki S.
المؤلفVeturi, Yogasudha
المؤلفPacheco, Jennifer Allen
المؤلفRosenthal, Elisabeth A.
المؤلفLingren, Todd
المؤلفFeng, Qi Ping
المؤلفKullo, Iftikhar J.
المؤلفNarita, Akira
المؤلفTakayama, Jun
المؤلفMartin, Hilary C.
المؤلفHunt, Karen A.
المؤلفTrivedi, Bhavi
المؤلفHaessler, Jeffrey
المؤلفGiulianini, Franco
المؤلفBradford, Yuki
المؤلفMiller, Jason E.
المؤلفCampbell, Archie
المؤلفLin, Kuang
المؤلفMillwood, Iona Y.
المؤلفRasheed, Asif
المؤلفHindy, George
المؤلفFaul, Jessica D.
المؤلفZhao, Wei
المؤلفWeir, David R.
المؤلفTurman, Constance
المؤلفHuang, Hongyan
المؤلفGraff, Mariaelisa
المؤلفChoudhury, Ananyo
المؤلفSengupta, Dhriti
المؤلفMahajan, Anubha
المؤلفBrown, Michael R.
المؤلفZhang, Weihua
المؤلفYu, Ketian
المؤلفSchmidt, Ellen M.
المؤلفPandit, Anita
المؤلفGustafsson, Stefan
المؤلفYin, Xianyong
المؤلفLuan, Jian'an
المؤلفZhao, Jing Hua
المؤلفMatsuda, Fumihiko
المؤلفJang, Hye Mi
المؤلفYoon, Kyungheon
المؤلفMedina-Gomez, Carolina
المؤلفPitsillides, Achilleas
المؤلفHottenga, Jouke Jan
المؤلفWood, Andrew R.
المؤلفJi, Yingji
المؤلفGao, Zishan
المؤلفHaworth, Simon
المؤلفMitchell, Ruth E.
المؤلفChai, Jin Fang
المؤلفAadahl, Mette
المؤلفBjerregaard, Anne A.
المؤلفYao, Jie
المؤلفManichaikul, Ani
المؤلفLee, Wen Jane
المؤلفHsiung, Chao Agnes
المؤلفWarren, Helen R.
المؤلفRamirez, Julia
المؤلفBork-Jensen, Jette
المؤلفKårhus, Line L.
المؤلفGoel, Anuj
المؤلفSabater-Lleal, Maria
تاريخ الإتاحة2023-05-09T10:54:18Z
تاريخ النشر2022-08-04
اسم المنشورAmerican Journal of Human Genetics
المعرّفhttp://dx.doi.org/10.1016/j.ajhg.2022.06.012
الرقم المعياري الدولي للكتاب00029297
معرّف المصادر الموحدhttps://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85135598739&origin=inward
معرّف المصادر الموحدhttp://hdl.handle.net/10576/42514
الملخصA 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.
راعي المشروعXiang Zhu is supported by the Stein Fellowship from Stanford University and Institute for Computational and Data Sciences Seed Grant from The Pennsylvania State University. C.D.B. is supported by the NIH (R01-HL133218). Funding for the Global Lipids Genetics Consortium was provided by the NIH (R01-HL127564). This research was conducted using the UK Biobank Resource under application number 24460. This research is based on data from the Million Veteran Program, Office of Research and Development, Veterans Health Administration, and was supported by awards 2I01BX003362-03A1 and 1I01BX004821-01A1. This publication does not represent the views of the Department of Veteran Affairs or the United States Government. We thank Bethany Klunder for administrative support. Study-specific acknowledgments are provided in the supplemental information.
اللغةen
الناشرElsevier
الموضوعcomplex traits
fine-mapping
functional genomics
lipid biology
post-GWAS
regulatory mechanism
variant prioritization
العنوانA multi-layer functional genomic analysis to understand noncoding genetic variation in lipids
النوعArticle
الصفحات1366-1387
رقم العدد8
رقم المجلد109
dc.accessType Open Access


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