Genetic fine mapping and genomic annotation defines causal mechanisms at type 2 diabetes susceptibility loci

Kyle J Gaulton; Teresa Ferreira; Yeji Lee; Anne Raimondo; Reedik Mägi; Michael E Reschen; Anubha Mahajan; Adam Locke; N William Rayner; Neil Robertson; Robert A Scott; Inga Prokopenko; Laura J Scott; Todd Green; Thomas Sparso; Dorothee Thuillier; Loic Yengo; Harald Grallert; Simone Wahl; Mattias Frånberg; Rona J Strawbridge; Hans Kestler; Himanshu Chheda; Lewin Eisele; Stefan Gustafsson; Valgerdur Steinthorsdottir; Gudmar Thorleifsson; Lu Qi; Lennart C Karssen; Elisabeth M van Leeuwen; Sara M Willems; Man Li; Han Chen; Christian Fuchsberger; Phoenix Kwan; Clement Ma; Michael Linderman; Yingchang Lu; Soren K Thomsen; Jana K Rundle; Nicola L Beer; Martijn van de Bunt; Anil Chalisey; Hyun Min Kang; Benjamin F Voight; Gonçalo R Abecasis; Peter Almgren; Damiano Baldassarre; Beverley Balkau; Rafn Benediktsson; Matthias Blüher; Heiner Boeing; Lori L Bonnycastle; Erwin P Bottinger; Noël P Burtt; Jason Carey; Guillaume Charpentier; Peter S Chines; Marilyn C Cornelis; David J Couper; Andrew T Crenshaw; Rob M van Dam; Alex S F Doney; Mozhgan Dorkhan; Sarah Edkins; Johan G Eriksson; Tonu Esko; Elodie Eury; João Fadista; Jason Flannick; Pierre Fontanillas; Caroline Fox; Paul W Franks; Karl Gertow; Christian Gieger; Bruna Gigante; Omri Gottesman; George B Grant; Niels Grarup; Christopher J Groves; Maija Hassinen; Christian T Have; Christian Herder; Oddgeir L Holmen; Astradur B Hreidarsson; Steve E Humphries; David J Hunter; Anne U Jackson; Anna Jonsson; Marit E Jørgensen; Torben Jørgensen; Wen-Hong L Kao; Nicola D Kerrison; Leena Kinnunen; Norman Klopp; Augustine Kong; Peter Kovacs; Peter Kraft; Jasmina Kravic; Cordelia Langford; DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) Consortium

doi:10.1038/ng.3437

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Genetic fine mapping and genomic annotation defines causal mechanisms at type 2 diabetes susceptibility loci

Journal article

Peer reviewed

Genetic fine mapping and genomic annotation defines causal mechanisms at type 2 diabetes susceptibility loci

Kyle J Gaulton, Teresa Ferreira, Yeji Lee, Anne Raimondo, Reedik Mägi, Michael E Reschen, Anubha Mahajan, Adam Locke, N William Rayner, Neil Robertson, …

Nature genetics, Vol.47(12), pp.1415-1425

01/12/2015

DOI: https://doi.org/10.1038/ng.3437

PMID: 26551672

Abstract

Binding Sites

Case-Control Studies

Chromatin Immunoprecipitation

Chromosome Mapping

Diabetes Mellitus, Type 2 - genetics

Gene Expression Regulation

Genetic Loci

Genetic Predisposition to Disease

Genome-Wide Association Study

Genomics

Hepatocyte Nuclear Factor 3-beta - genetics

Hepatocyte Nuclear Factor 3-beta - metabolism

Humans

Islets of Langerhans - metabolism

Islets of Langerhans - pathology

Liver - metabolism

Liver - pathology

Molecular Sequence Annotation

Polymorphism, Single Nucleotide - genetics

Receptor, Melatonin, MT2 - genetics

Receptor, Melatonin, MT2 - metabolism

We performed fine mapping of 39 established type 2 diabetes (T2D) loci in 27,206 cases and 57,574 controls of European ancestry. We identified 49 distinct association signals at these loci, including five mapping in or near KCNQ1. 'Credible sets' of the variants most likely to drive each distinct signal mapped predominantly to noncoding sequence, implying that association with T2D is mediated through gene regulation. Credible set variants were enriched for overlap with FOXA2 chromatin immunoprecipitation binding sites in human islet and liver cells, including at MTNR1B, where fine mapping implicated rs10830963 as driving T2D association. We confirmed that the T2D risk allele for this SNP increases FOXA2-bound enhancer activity in islet- and liver-derived cells. We observed allele-specific differences in NEUROD1 binding in islet-derived cells, consistent with evidence that the T2D risk allele increases islet MTNR1B expression. Our study demonstrates how integration of genetic and genomic information can define molecular mechanisms through which variants underlying association signals exert their effects on disease.

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Title: Genetic fine mapping and genomic annotation defines causal mechanisms at type 2 diabetes susceptibility loci
Creators: Kyle J Gaulton - Wellcome Centre for Human Genetics
Teresa Ferreira - Wellcome Centre for Human Genetics
Yeji Lee - University of Michigan–Ann Arbor
Anne Raimondo - Oxford Centre for Diabetes, Endocrinology and Metabolism
Reedik Mägi - University of Tartu
Michael E Reschen - University of Oxford
Anubha Mahajan - University of Oxford
Adam Locke - University of Michigan–Ann Arbor
N William Rayner - Wellcome Centre for Human Genetics
Neil Robertson - University of Oxford
Robert A Scott - University of Cambridge
Inga Prokopenko - Imperial College London
Laura J Scott - University of Michigan–Ann Arbor
Todd Green - Broad Institute
Thomas Sparso - University of Copenhagen
Dorothee Thuillier - European Genomic Institute for Diabetes
Loic Yengo - European Genomic Institute for Diabetes
Harald Grallert - Helmholtz Zentrum München
Simone Wahl - Helmholtz Zentrum München
Mattias Frånberg - Karolinska Institutet
Rona J Strawbridge - Karolinska Institutet
Hans Kestler - Leibniz Institute on Aging - Fritz Lipmann Institute (FLI)
Himanshu Chheda - Institute for Molecular Medicine Finland
Lewin Eisele - Institut für Medizinische Informatik, Biometrie und Epidemiologie
Stefan Gustafsson - Uppsala University
Valgerdur Steinthorsdottir - deCODE Genetics/Amgen, Inc., Reykjavik, Iceland
Gudmar Thorleifsson - deCODE Genetics/Amgen, Inc., Reykjavik, Iceland
Lu Qi - Harvard University
Lennart C Karssen - Erasmus MC
Elisabeth M van Leeuwen - Erasmus MC
Sara M Willems - University of Cambridge
Man Li - Johns Hopkins University
Han Chen - Boston University
Christian Fuchsberger - University of Michigan–Ann Arbor
Phoenix Kwan - University of Michigan–Ann Arbor
Clement Ma - University of Michigan–Ann Arbor
Michael Linderman - Icahn School of Medicine at Mount Sinai
Yingchang Lu - Icahn School of Medicine at Mount Sinai
Soren K Thomsen - Oxford Centre for Diabetes, Endocrinology and Metabolism
Jana K Rundle - Oxford Centre for Diabetes, Endocrinology and Metabolism
Nicola L Beer - Oxford Centre for Diabetes, Endocrinology and Metabolism
Martijn van de Bunt - Oxford Centre for Diabetes, Endocrinology and Metabolism
Anil Chalisey - University of Oxford
Hyun Min Kang - University of Michigan–Ann Arbor
Benjamin F Voight - University of Pennsylvania
Gonçalo R Abecasis - University of Michigan–Ann Arbor
Peter Almgren - Scania
Damiano Baldassarre - Centro Cardiologico Monzino
Beverley Balkau - Centre de recherche en Epidémiologie et Santé des Populations
Rafn Benediktsson - University of Iceland
Matthias Blüher - IFB Adiposity Diseases
Heiner Boeing - German Institute of Human Nutrition
Lori L Bonnycastle - National Human Genome Research Institute
Erwin P Bottinger - Icahn School of Medicine at Mount Sinai
Noël P Burtt - Broad Institute
Jason Carey - Broad Institute
Guillaume Charpentier - Centre Hospitalier Sud Francilien
Peter S Chines - National Human Genome Research Institute
Marilyn C Cornelis - Northwestern University
David J Couper - University of North Carolina at Chapel Hill
Andrew T Crenshaw - Broad Institute
Rob M van Dam - Harvard University
Alex S F Doney - Ninewells Hospital
Mozhgan Dorkhan - Lund University
Sarah Edkins - Wellcome Sanger Institute
Johan G Eriksson - Finnish Institute for Health and Welfare
Tonu Esko - University of Tartu
Elodie Eury - Institut Pasteur de Lille
João Fadista - Scania
Jason Flannick - Broad Institute
Pierre Fontanillas - Broad Institute
Caroline Fox - Framingham Heart Study
Paul W Franks - Harvard University
Karl Gertow - Karolinska Institutet
Christian Gieger - Helmholtz Zentrum München
Bruna Gigante - Karolinska Institutet
Omri Gottesman - Icahn School of Medicine at Mount Sinai
George B Grant - Broad Institute
Niels Grarup - University of Copenhagen
Christopher J Groves - Oxford Centre for Diabetes, Endocrinology and Metabolism
Maija Hassinen - University of Eastern Finland
Christian T Have - University of Copenhagen
Christian Herder - Deutsches Diabetes-Zentrum e.V.
Oddgeir L Holmen - Norwegian University of Science and Technology
Astradur B Hreidarsson - Landspitali University Hospital, Reykjavik, Iceland
Steve E Humphries - British Heart Foundation
David J Hunter - Program in Genetic Epidemiology and Statistical Genetics, Harvard School of Public Health, Boston, Massachusetts, USA
Anne U Jackson - University of Michigan–Ann Arbor
Anna Jonsson - Scania
Marit E Jørgensen - Steno Diabetes Center
Torben Jørgensen - Capital Region of Denmark
Wen-Hong L Kao - Johns Hopkins Bloomberg School of Public Health
Nicola D Kerrison - Medical Research Council
Leena Kinnunen - Finnish Institute for Health and Welfare
Norman Klopp - Helmholtz Zentrum München
Augustine Kong - deCODE Genetics
Peter Kovacs - IFB Adiposity Diseases
Peter Kraft - Harvard University
Jasmina Kravic - Scania
Cordelia Langford - Wellcome Sanger Institute
DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) Consortium
Publication Details: Nature genetics, Vol.47(12), pp.1415-1425
Date published: 01/12/2015
Grant note: R01 DK062370 / NIDDK NIH HHS HHSN268200625226C / PHS HHS PG/11/4/28645 / British Heart Foundation U01 DK078616 / NIDDK NIH HHS HHSN268201100007C / NHLBI NIH HHS R01 DK072193 / NIDDK NIH HHS U01 HG004402 / NHGRI NIH HHS U01 DK085545 / NIDDK NIH HHS HHSN268201100005G / NHLBI NIH HHS 090532 / Wellcome Trust
Identifiers: 99928585302346
Academic Unit: School of Biosciences
Language: English
Resource Type: Journal article

Genetic fine mapping and genomic annotation defines causal mechanisms at type 2 diabetes susceptibility loci

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