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

Research output: Contribution to journalArticle

Abstract

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.

Details

Authors
  • 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
  • Sarah Edkins
  • Johan G Eriksson
  • Tonu Esko
  • Elodie Eury
  • Joao Fadista
  • Jason Flannick
  • Pierre Fontanillas
  • Caroline Fox
  • 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
  • Cordelia Langford
  • Karin Leander
  • Liming Liang
  • Peter Lichtner
  • Cecilia M Lindgren
  • Allan Linneberg
  • Ching-Ti Liu
  • Stéphane Lobbens
  • Jian'an Luan
  • Satu Männistö
  • Olga McLeod
  • Julia Meyer
  • Evelin Mihailov
  • Ghazala Mirza
  • Thomas W Mühleisen
  • Martina Müller-Nurasyid
  • Carmen Navarro
  • Markus M Nöthen
  • 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
  • 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
Organisations
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Medical Genetics
Original languageEnglish
Pages (from-to)1415
JournalNature Genetics
Volume47
Issue number12
Publication statusPublished - 2015
Publication categoryResearch
Peer-reviewedYes