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Large-scale exome array summary statistics resources for glycemic traits to aid effector gene prioritization.
Willems, Sara M; Ng, Natasha H J; Fernandez, Juan; Fine, Rebecca S; Wheeler, Eleanor; Wessel, Jennifer; Kitajima, Hidetoshi; Marenne, Gaelle; Sim, Xueling; Yaghootkar, Hanieh; Wang, Shuai; Chen, Sai; Chen, Yuning; Chen, Yii-Der Ida; Grarup, Niels; Li-Gao, Ruifang; Varga, Tibor V; Asimit, Jennifer L; Feng, Shuang; Strawbridge, Rona J; Kleinbrink, Erica L; Ahluwalia, Tarunveer S; An, Ping; Appel, Emil V; Arking, Dan E; Auvinen, Juha; Bielak, Lawrence F; Bihlmeyer, Nathan A; Bork-Jensen, Jette; Brody, Jennifer A; Campbell, Archie; Chu, Audrey Y; Davies, Gail; Demirkan, Ayse; Floyd, James S; Giulianini, Franco; Guo, Xiuqing; Gustafsson, Stefan; Jackson, Anne U; Jakobsdottir, Johanna; Järvelin, Marjo-Riitta; Jensen, Richard A; Kanoni, Stavroula; Keinanen-Kiukaanniemi, Sirkka; Li, Man; Lu, Yingchang; Luan, Jian'an; Manning, Alisa K; Marten, Jonathan; Meidtner, Karina.
Afiliação
  • Willems SM; MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Institute of Metabolic Science, Cambridge Biomedical Campus, Cambridge, CB2 0QQ, UK.
  • Ng NHJ; General Medicine Center, Saarland University Faculty of Medicine, Homburg, 66421, Germany.
  • Fernandez J; Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, OX3 7LE, UK.
  • Fine RS; Stem Cells and Diabetes Laboratory, Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), Singapore, 138673, Singapore.
  • Wheeler E; Wellcome Centre for Human Genetics, University of Oxford, Oxford, OX3 7BN, UK.
  • Wessel J; Department of Genetics, Harvard Medical School, Boston, MA, 02115, USA.
  • Kitajima H; Division of Endocrinology and Center for Basic and Translational Obesity Research, Boston Children's Hospital, Boston, MA, 02115, USA.
  • Marenne G; Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA.
  • Sim X; Current address: Vertex Pharmaceuticals Incorporated, 50 Northern Avenue, Boston, MA, 02210, USA.
  • Yaghootkar H; MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Institute of Metabolic Science, Cambridge Biomedical Campus, Cambridge, CB2 0QQ, UK.
  • Wang S; Department of Human Genetics, Wellcome Sanger Institute, Genome Campus, Hinxton, Cambridge, CB10 1SA, UK.
  • Chen S; Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA.
  • Chen Y; Departments of Epidemiology & Medicine, Schools of Public Health & Medicine, Indiana University, Indianapolis, IN, 46202, USA.
  • Chen YI; Diabetes Translational Research Center, Indiana University School of Medicine, Indianapolis, IN, 46202, USA.
  • Grarup N; General Medicine Division, Massachusetts General Hospital, Boston, MA, USA.
  • Li-Gao R; Wellcome Centre for Human Genetics, University of Oxford, Oxford, OX3 7BN, UK.
  • Varga TV; Department of Human Genetics, Wellcome Sanger Institute, Genome Campus, Hinxton, Cambridge, CB10 1SA, UK.
  • Asimit JL; Saw Swee Hock School of Public Health, National University Health System, National University of Singapore, Singapore, 117549, Singapore.
  • Feng S; Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, MI, 48109, USA.
  • Strawbridge RJ; Genetics of Complex Traits, University of Exeter Medical School, University of Exeter, Exeter, EX2 5DW, UK.
  • Kleinbrink EL; Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA.
  • Ahluwalia TS; Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, MI, 48109, USA.
  • An P; Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA.
  • Appel EV; The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, 90502, USA.
  • Arking DE; Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, 2200, Denmark.
  • Auvinen J; Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, 2333 ZA, The Netherlands.
  • Bielak LF; Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Lund University, Malmö, SE-205 02, Sweden.
  • Bihlmeyer NA; Department of Human Genetics, Wellcome Sanger Institute, Genome Campus, Hinxton, Cambridge, CB10 1SA, UK.
  • Bork-Jensen J; MRC Biostatistics Unit, University of Cambridge, Cambridge, CB2 0SR, UK.
  • Brody JA; Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, MI, USA.
  • Campbell A; Mental Health and Wellbeing, School of Health and Wellbeing, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, G12 8RZ, UK.
  • Chu AY; Cardiovascular Medicine Unit, Department of Medicine Solna, Karolinska Institute, Stockholm, 171 76, Sweden.
  • Davies G; Quantitative Life Sciences, McGill University, Montreal, Quebec, Canada.
  • Demirkan A; Center for Molecular Medicine and Genetics, Wayne State University, Detroit, MI, 48201-1928, USA.
  • Floyd JS; COPSAC, Copenhagen Prospective Studies on Asthma in Childhood, Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark.
  • Giulianini F; Steno Diabetes Center Copenhagen, Gentofte, 2820, Denmark.
  • Guo X; Department of Genetics, Division of Statistical Genomics, Washington University School of Medicine, St. Louis, Missouri, 63108, USA.
  • Gustafsson S; Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, 2200, Denmark.
  • Jackson AU; McKusick-Nathans Institute, Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • Jakobsdottir J; Center for Life Course Health Research, University of Oulu, Oulu, 90014, Finland.
  • Järvelin MR; Unit of Primary Care, Oulu University Hospital, Oulu, Finland.
  • Jensen RA; Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI, 48109, USA.
  • Kanoni S; McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • Keinanen-Kiukaanniemi S; Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, 2200, Denmark.
  • Li M; Cardiovascular Health Research Unit, University of Washington, Seattle, WA, 98195, USA.
  • Lu Y; Department of Medicine, University of Washington, Seattle, WA, USA.
  • Luan J; Centre for Genomic and Experimental Medicine, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, EH4 2XU, UK.
  • Manning AK; Division of Preventive Medicine, Brigham and Women's Hospital, Boston, MA, 02215, USA.
  • Marten J; Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, EH8 9JZ, UK.
  • Meidtner K; Department of Psychology, University of Edinburgh, Edinburgh, EH8 9JZ, UK.
Wellcome Open Res ; 8: 483, 2023.
Article em En | MEDLINE | ID: mdl-39280063
ABSTRACT

Background:

Genome-wide association studies for glycemic traits have identified hundreds of loci associated with these biomarkers of glucose homeostasis. Despite this success, the challenge remains to link variant associations to genes, and underlying biological pathways.

Methods:

To identify coding variant associations which may pinpoint effector genes at both novel and previously established genome-wide association loci, we performed meta-analyses of exome-array studies for four glycemic traits glycated hemoglobin (HbA1c, up to 144,060 participants), fasting glucose (FG, up to 129,665 participants), fasting insulin (FI, up to 104,140) and 2hr glucose post-oral glucose challenge (2hGlu, up to 57,878). In addition, we performed network and pathway analyses.

Results:

Single-variant and gene-based association analyses identified coding variant associations at more than 60 genes, which when combined with other datasets may be useful to nominate effector genes. Network and pathway analyses identified pathways related to insulin secretion, zinc transport and fatty acid metabolism. HbA1c associations were strongly enriched in pathways related to blood cell biology.

Conclusions:

Our results provided novel glycemic trait associations and highlighted pathways implicated in glycemic regulation. Exome-array summary statistic results are being made available to the scientific community to enable further discoveries.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Idioma: En Revista: Wellcome Open Res Ano de publicação: 2023 Tipo de documento: Article País de publicação: Reino Unido
Texto completo
Adicionar na Minha BVS
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Idioma: En Revista: Wellcome Open Res Ano de publicação: 2023 Tipo de documento: Article País de publicação: Reino Unido