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; Karin Leander; Liming Liang; Peter Lichtner; Cecilia M Lindgren; Eero Lindholm; Allan Linneberg; Ching-Ti Liu; Stéphane Lobbens; Jian'an Luan; Valeriya Lyssenko; Satu Männistö; Olga McLeod; Julia Meyer; Evelin Mihailov; Ghazala Mirza; Thomas W Mühleisen; Martina Müller-Nurasyid; Carmen Navarro; Markus M Nöthen; Nikolay N Oskolkov; Katharine R Owen; Domenico Palli; Sonali Pechlivanis; Leena Peltonen; John R B Perry; Carl G P Platou; Michael Roden; Douglas Ruderfer; Denis Rybin; Yvonne T van der Schouw; Bengt Sennblad; Gunnar Sigurðsson; Alena Stančáková; Gerald Steinbach; Petter Storm; Konstantin Strauch; Heather M Stringham; Qi Sun; Barbara Thorand; Emmi Tikkanen; Anke Tonjes; Joseph Trakalo; Elena Tremoli; Tiinamaija Tuomi; Roman Wennauer; Steven Wiltshire; Andrew R Wood; Eleftheria Zeggini; Ian Dunham; Ewan Birney; Lorenzo Pasquali; Jorge Ferrer; Ruth J F Loos; Josée Dupuis; Jose C Florez; Eric Boerwinkle; James S Pankow; Cornelia van Duijn; Eric Sijbrands; James B Meigs; Frank B Hu; Unnur Thorsteinsdottir; Kari Stefansson; Timo A Lakka; Rainer Rauramaa; Michael Stumvoll; Nancy L Pedersen; Lars Lind; Sirkka M Keinanen-Kiukaanniemi; Eeva Korpi-Hyövälti; Timo E Saaristo; Juha Saltevo; Johanna Kuusisto; Markku Laakso; Andres Metspalu; Raimund Erbel; Karl-Heinz Jöcke; Susanne Moebus; Samuli Ripatti; Veikko Salomaa; Erik Ingelsson; Bernhard O Boehm; Richard N Bergman; Francis S Collins; Karen L Mohlke; Heikki Koistinen; Jaakko Tuomilehto; Kristian Hveem; Inger Njølstad; Panagiotis Deloukas; Peter J Donnelly; Timothy M Frayling; Andrew T Hattersley; Ulf de Faire; Anders Hamsten; Thomas Illig; Annette Peters; Stephane Cauchi; Rob Sladek; Philippe Froguel; Torben Hansen; Oluf Pedersen; Andrew D Morris; Collin N A Palmer; Sekar Kathiresan; Olle Melander; Peter M Nilsson; Leif C Groop; Inês Barroso; Claudia Langenberg; Nicholas J Wareham; Christopher A O'Callaghan; Anna L Gloyn; David Altshuler; Michael Boehnke; Tanya M Teslovich; Mark I McCarthy; Andrew P Morris; 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-+

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 - without role: Kyle J Gaulton - Stanford University
Teresa Ferreira - University of Oxford
Yeji Lee - University of Michigan–Ann Arbor
Anne Raimondo - University of Oxford
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 Sanger Institute
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 - Genomics
Loic Yengo - Genomics
Harald Grallert - German Center for Diabetes Research
Simone Wahl - German Center for Diabetes Research
Mattias Frånberg - Stockholm University
Rona J Strawbridge - Karolinska Institutet
Hans Kestler - University of Ulm
Himanshu Chheda - Finnish Institute for Molecular Medicine (FIMM), Helsinki, Finland
Lewin Eisele - Institute for Medical Informatics, Biometry and Epidemiology, University Hospital of Essen, Essen, Germany
Stefan Gustafsson - Uppsala University
Valgerdur Steinthorsdottir - deCODE Genetics/Amgen, Inc., Reykjavik, Iceland
Gudmar Thorleifsson - deCODE Genetics/Amgen, Inc., Reykjavik, Iceland
Lu Qi - University of New Orleans
Lennart C Karssen - Erasmus MC
Elisabeth M van Leeuwen - Erasmus MC
Sara M Willems - Erasmus MC
Man Li - Bloomberg
Han Chen - Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts, USA
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 - University of Oxford
Jana K Rundle - University of Oxford
Nicola L Beer - University of Oxford
Martijn van de Bunt - University of Oxford
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 - Lund University
Damiano Baldassarre - Mylan
Beverley Balkau - University of Paris-Sud
Rafn Benediktsson - Landspitali University Hospital, Reykjavik, Iceland
Matthias Blüher - Department of Medicine, University of Leipzig, Leipzig, Germany
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 - Endocrinology-Diabetology Unit, Corbeil-Essonnes Hospital, Corbeil-Essonnes, France
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 - Duke-NUS Medical School
Alex S F Doney - University of Dundee
Mozhgan Dorkhan - Lund University
Sarah Edkins - Wellcome Sanger Institute
Johan G Eriksson - Folkhalsan Research Center, Helsinki, Finland
Tonu Esko - Broad Institute
Elodie Eury - Pasteur Institute of Lille
João Fadista - Lund University
Jason Flannick - Broad Institute
Pierre Fontanillas - Broad Institute
Caroline Fox - Brigham and Women's Hospital
Paul W Franks - Umeå 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 - University of Oxford
Maija Hassinen - Kuopio Research Institute of Exercise Medicine, Kuopio, Finland
Christian T Have - University of Copenhagen
Christian Herder - German Center for Diabetes Research
Oddgeir L Holmen - Norwegian University of Science and Technology
Astradur B Hreidarsson - Landspitali University Hospital, Reykjavik, Iceland
Steve E Humphries - UCL Australia
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 - Lund University
Marit E Jørgensen - Steno Diabetes Center
Torben Jørgensen - Faculty
Wen-Hong L Kao - Bloomberg
Nicola D Kerrison - University of Cambridge
Leena Kinnunen - Department of Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki, Finland
Norman Klopp - Medizinische Hochschule Hannover
Augustine Kong - deCODE Genetics/Amgen, Inc., Reykjavik, Iceland
Peter Kovacs - Department of Medicine, University of Leipzig, Leipzig, Germany
Peter Kraft - Program in Genetic Epidemiology and Statistical Genetics, Harvard School of Public Health, Boston, Massachusetts, USA
Jasmina Kravic - Lund University
Cordelia Langford - Wellcome Sanger Institute
Karin Leander - Karolinska Institutet
Liming Liang - Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts, USA
Peter Lichtner - Helmholtz Zentrum München
Cecilia M Lindgren - Broad Institute
Eero Lindholm - Lund University
Allan Linneberg - University of Copenhagen
Ching-Ti Liu - Boston University
Stéphane Lobbens - Pasteur Institute of Lille
Jian'an Luan - University of Cambridge
Valeriya Lyssenko - Steno Diabetes Center
Satu Männistö - Department of Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki, Finland
Olga McLeod - Karolinska Institutet
Julia Meyer - Helmholtz Zentrum München
Evelin Mihailov - University of Tartu
Ghazala Mirza - St Thomas' Hospital
Thomas W Mühleisen - Institute of Neuroscience and Medicine (INM-1), Research Centre Jülich, Jülich, Germany
Martina Müller-Nurasyid - DZHK (German Center for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany
Carmen Navarro - Department of Health and Social Sciences, Universidad de Murcia, Murcia, Spain
Markus M Nöthen - University of Bonn
Nikolay N Oskolkov - Lund University
Katharine R Owen - Churchill Hospital
Domenico Palli - Florence
Sonali Pechlivanis - Institute for Medical Informatics, Biometry and Epidemiology, University Hospital of Essen, Essen, Germany
Leena Peltonen - Department of Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki, Finland
John R B Perry - University of Cambridge
Carl G P Platou - Levanger Hospital
Michael Roden - Department of Endocrinology and Diabetology, University Hospital Dusseldorf, Dusseldorf, Germany
Douglas Ruderfer - Icahn School of Medicine at Mount Sinai
Denis Rybin - Boston University
Yvonne T van der Schouw - University Medical Center Utrecht
Bengt Sennblad - Science for Life Laboratory, Stockholm, Sweden
Gunnar Sigurðsson - Icelandic Heart Association
Alena Stančáková - University of Eastern Finland
Gerald Steinbach - University of Ulm
Petter Storm - Lund University
Konstantin Strauch - Institute of Medical Informatics, Biometry and Epidemiology, Chair of Genetic Epidemiology, Ludwig Maximilians Universität, Neuherberg, Germany
Heather M Stringham - University of Michigan–Ann Arbor
Qi Sun - Brigham and Women's Hospital
Barbara Thorand - German Center for Diabetes Research
Emmi Tikkanen - University of Helsinki
Anke Tonjes - Department of Medicine, University of Leipzig, Leipzig, Germany
Joseph Trakalo - University of Oxford
Elena Tremoli - Mylan
Tiinamaija Tuomi - University of Helsinki
Roman Wennauer - Erasmus MC
Steven Wiltshire - University of Oxford
Andrew R Wood - University of Exeter
Eleftheria Zeggini - Wellcome Sanger Institute
Ian Dunham - European Bioinformatics Institute
Ewan Birney - European Bioinformatics Institute
Lorenzo Pasquali - CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Barcelona, Spain
Jorge Ferrer - Pi
Ruth J F Loos - Icahn School of Medicine at Mount Sinai
Josée Dupuis - National Heart Lung and Blood Institute
Jose C Florez - Massachusetts General Hospital
Eric Boerwinkle - Baylor College of Medicine
James S Pankow - University of Minnesota
Cornelia van Duijn - Netherlands Consortium for Healthy Ageing
Eric Sijbrands - Erasmus MC
James B Meigs - Massachusetts General Hospital
Frank B Hu - Brigham and Women's Hospital
Unnur Thorsteinsdottir - University of Iceland
Kari Stefansson - University of Iceland
Timo A Lakka - Kuopio University Hospital
Rainer Rauramaa - Kuopio University Hospital
Michael Stumvoll - Department of Medicine, University of Leipzig, Leipzig, Germany
Nancy L Pedersen - Karolinska Institutet
Lars Lind - Uppsala University Hospital
Sirkka M Keinanen-Kiukaanniemi - Oulu University Hospital
Eeva Korpi-Hyövälti - South Ostrobothnia Central Hospital, Seinajoki, Finland
Timo E Saaristo - Pirkanmaa District Hospital, Tampere, Finland
Juha Saltevo - Department of Medicine, Central Finland Central Hospital, Jyvasklya, Finland
Johanna Kuusisto - University of Eastern Finland
Markku Laakso - University of Eastern Finland
Andres Metspalu - University of Tartu
Raimund Erbel - Clinic of Cardiology, West German Heart Centre, University Hospital of Essen, University Duisdurg-Essen, Essen, Germany
Karl-Heinz Jöcke - University of Eastern Finland
Susanne Moebus - Institute for Medical Informatics, Biometry and Epidemiology, University Hospital of Essen, Essen, Germany
Samuli Ripatti - Genomics
Veikko Salomaa - Department of Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki, Finland
Erik Ingelsson - Uppsala University
Bernhard O Boehm - Nanyang Technological University
Richard N Bergman - Cedars-Sinai Medical Center
Francis S Collins - National Human Genome Research Institute
Karen L Mohlke - University of North Carolina at Chapel Hill
Heikki Koistinen - Minerva Foundation
Jaakko Tuomilehto - King Abdulaziz University
Kristian Hveem - Norwegian University of Science and Technology
Inger Njølstad - Faculty
Panagiotis Deloukas - Queen Mary University of London
Peter J Donnelly - University of Oxford
Timothy M Frayling - University of Exeter
Andrew T Hattersley - University of Exeter
Ulf de Faire - Karolinska Institutet
Anders Hamsten - Karolinska Institutet
Thomas Illig - Medizinische Hochschule Hannover
Annette Peters - DZHK (German Center for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany
Stephane Cauchi - Genomics
Rob Sladek - McGill University and Génome Québec Innovation Centre
Philippe Froguel - Pasteur Institute of Lille
Torben Hansen - University of Southern Denmark
Oluf Pedersen - University of Copenhagen
Andrew D Morris - University of Edinburgh
Collin N A Palmer - University of Dundee
Sekar Kathiresan - Massachusetts General Hospital
Olle Melander - Lund University
Peter M Nilsson - Lund University
Leif C Groop - Lund University
Inês Barroso - National Institute for Health Research Cambridge Biomedical Research Centre, Cambridge, UK
Claudia Langenberg - University of Cambridge
Nicholas J Wareham - University of Cambridge
Christopher A O'Callaghan - University of Oxford
Anna L Gloyn - Churchill Hospital
David Altshuler - Harvard Medical School
Michael Boehnke - University of Michigan–Ann Arbor
Tanya M Teslovich - University of Michigan–Ann Arbor
Mark I McCarthy - Churchill Hospital
Andrew P Morris - University of Liverpool
DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) Consortium
Publication Details: Nature genetics, Vol.47(12), pp.1415-+
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Identifiers: 9937078008331
Academic Unit: King Abdulaziz University
Language: English
Resource Type: Journal article