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A multi-layer functional genomic analysis to understand noncoding genetic variation in lipids.
Ramdas, Shweta; Judd, Jonathan; Graham, Sarah E; Kanoni, Stavroula; Wang, Yuxuan; Surakka, Ida; Wenz, Brandon; Clarke, Shoa L; Chesi, Alessandra; Wells, Andrew; Bhatti, Konain Fatima; Vedantam, Sailaja; Winkler, Thomas W; Locke, Adam E; Marouli, Eirini; Zajac, Greg J M; Wu, Kuan-Han H; Ntalla, Ioanna; Hui, Qin; Klarin, Derek; Hilliard, Austin T; Wang, Zeyuan; Xue, Chao; Thorleifsson, Gudmar; Helgadottir, Anna; Gudbjartsson, Daniel F; Holm, Hilma; Olafsson, Isleifur; Hwang, Mi Yeong; Han, Sohee; Akiyama, Masato; Sakaue, Saori; Terao, Chikashi; Kanai, Masahiro; Zhou, Wei; Brumpton, Ben M; Rasheed, Humaira; Havulinna, Aki S; Veturi, Yogasudha; Pacheco, Jennifer Allen; Rosenthal, Elisabeth A; Lingren, Todd; Feng, QiPing; Kullo, Iftikhar J; Narita, Akira; Takayama, Jun; Martin, Hilary C; Hunt, Karen A; Trivedi, Bhavi; Haessler, Jeffrey.
Afiliação
  • Ramdas S; Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
  • Judd J; Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA.
  • Graham SE; Department of Internal Medicine, Division of Cardiology, University of Michigan, Ann Arbor, MI 48109, USA.
  • Kanoni S; William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, John Vane Science Centre, Charterhouse Square, London EC1M 6BQ, UK.
  • Wang Y; Department of Biostatistics, Boston University School of Public Health, 801 Massachusetts Avenue, Boston, MA 02118, USA.
  • Surakka I; Department of Internal Medicine, Division of Cardiology, University of Michigan, Ann Arbor, MI 48109, USA.
  • Wenz B; Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
  • Clarke SL; VA Palo Alto Health Care Systems, Palo Alto, CA, USA; Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
  • Chesi A; Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • Wells A; Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
  • Bhatti KF; William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, John Vane Science Centre, Charterhouse Square, London EC1M 6BQ, UK.
  • Vedantam S; Endocrinology, Boston Childrens Hospital, Boston, MA 02115, USA; Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, 75 Ames street, Cambridge, MA 02142, USA.
  • Winkler TW; Department of Genetic Epidemiology, University of Regensburg, Regensburg, Germany.
  • Locke AE; McDonnell Genome Institute and Department of Medicine, Washington University, St. Louis, MO 63108, USA.
  • Marouli E; William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, John Vane Science Centre, Charterhouse Square, London EC1M 6BQ, UK.
  • Zajac GJM; Department of Biostatistics, Center for Statistical Genetics, University of Michigan, Ann Arbor, MI, USA.
  • Wu KH; Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA.
  • Ntalla I; Clinical Pharmacology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, EC1M 6BQ London, UK.
  • Hui Q; Department of Epidemiology, Emory University Rollins School of Public Health, Atlanta, GA, USA; Atlanta VA Health Care System, Decatur, GA, USA.
  • Klarin D; Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, 75 Ames street, Cambridge, MA 02142, USA; Malcolm Randall VA Medical Center, Gainesville, FL, USA; Division of Vascular Surgery and Endovascular Therapy, University of Florida College of Medicine, Gainesville, FL, USA.
  • Hilliard AT; VA Palo Alto Health Care Systems, Palo Alto, CA, USA.
  • Wang Z; Department of Epidemiology, Emory University Rollins School of Public Health, Atlanta, GA, USA; Atlanta VA Health Care System, Decatur, GA, USA.
  • Xue C; Department of Internal Medicine, Division of Cardiology, University of Michigan, Ann Arbor, MI 48109, USA.
  • Thorleifsson G; deCODE genetics/Amgen, Inc., Sturlugata 8, Reykjavik 102, Iceland.
  • Helgadottir A; deCODE genetics/Amgen, Inc., Sturlugata 8, Reykjavik 102, Iceland.
  • Gudbjartsson DF; deCODE genetics/Amgen, Inc., Sturlugata 8, Reykjavik 102, Iceland; School of Engineering and Natural Sciences, University of Iceland, Sæmundargötu 2, Reykjavik 102, Iceland.
  • Holm H; deCODE genetics/Amgen, Inc., Sturlugata 8, Reykjavik 102, Iceland.
  • Olafsson I; Department of Clinical Biochemistry, Landspitali - National University Hospital of Iceland, Hringbraut, Reykjavik 101, Iceland.
  • Hwang MY; Division of Genome Science, Department of Precision Medicine, National Institute of Health, Chungbuk, South Korea.
  • Han S; Division of Genome Science, Department of Precision Medicine, National Institute of Health, Chungbuk, South Korea.
  • Akiyama M; Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan; Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
  • Sakaue S; Department of Statistical Genetics, Osaka University Graduate School of Medicine, Osaka, Japan; Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, The University of Tokyo, Tokyo, Japan; Department of Allergy and Rheumatology, Graduate School of Medicine, The Universi
  • Terao C; Laboratory for Statistical and Translational Genetics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
  • Kanai M; Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, 75 Ames street, Cambridge, MA 02142, USA; Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan; Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA
  • Zhou W; Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, 75 Ames street, Cambridge, MA 02142, USA; Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA; Analytic and Translational Genetics Unit, Massachusetts General Hospital, Bos
  • Brumpton BM; K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, NTNU, Norwegian University of Science and Technology, Trondheim, Norway; MRC Integrative Epidemiology Unit (IEU), Bristol Medical School, University of Bristol, Oakfield House, Oakfield Grove, BS8 2BN Bristol, UK;
  • Rasheed H; K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, NTNU, Norwegian University of Science and Technology, Trondheim, Norway; MRC Integrative Epidemiology Unit (IEU), Bristol Medical School, University of Bristol, Oakfield House, Oakfield Grove, BS8 2BN Bristol, UK;
  • Havulinna AS; Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Tukholmankatu 8, 00014 Helsinki, Finland; Department of Public Health and Welfare, Finnish Institute for Health and Welfare, Helsinki, Finland.
  • Veturi Y; Department of Genetics, Institute for Biomedical Informatics, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19104, USA.
  • Pacheco JA; Center for Genetic Medicine, Northwestern University, Feinberg School of Medicine, Chicago, IL 60611, USA.
  • Rosenthal EA; Department of Medicine (Medical Genetics), University of Washington, Seattle, WA, USA.
  • Lingren T; Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
  • Feng Q; Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
  • Kullo IJ; Department of Cardiovascular Medicine and the Gonda Vascular Center, Mayo Clinic, Rochester, MN, USA.
  • Narita A; Tohoku Medical Megabank Organization, Tohoku University, Sendai 980-8573, Japan.
  • Takayama J; Tohoku Medical Megabank Organization, Tohoku University, Sendai 980-8573, Japan.
  • Martin HC; Wellcome Trust Sanger Institute, CB10 1SA Hinxton, UK.
  • Hunt KA; Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
  • Trivedi B; Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
  • Haessler J; Fred Hutchinson Cancer Research Center, Division of Public Health Sciences, Seattle, WA 98109, USA.
Am J Hum Genet ; 109(8): 1366-1387, 2022 08 04.
Article em En | MEDLINE | ID: mdl-35931049
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.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Polimorfismo de Nucleotídeo Único / Estudo de Associação Genômica Ampla Tipo de estudo: Prognostic_studies Limite: Humans Idioma: En Revista: Am J Hum Genet Ano de publicação: 2022 Tipo de documento: Article
Texto completo
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Polimorfismo de Nucleotídeo Único / Estudo de Associação Genômica Ampla Tipo de estudo: Prognostic_studies Limite: Humans Idioma: En Revista: Am J Hum Genet Ano de publicação: 2022 Tipo de documento: Article