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

Authors:
Dr Anubha Mahajan, PhD
Dr Anubha Mahajan, PhD
Wellcome Trust Centre for Human Genetics, University of Oxford
UK
Kyle J Gaulton Teresa Ferreira Yeji Lee Anne Raimondo Reedik Mägi Michael E Reschen 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

Nat Genet 2015 Dec 9;47(12):1415-25. Epub 2015 Nov 9.

Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.

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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http://dx.doi.org/10.1038/ng.3437DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4666734PMC
December 2015
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