Fine-mapping type 2 diabetes loci to single-variant resolution using high-density imputation and islet-specific epigenome maps

Anubha Mahajan; Daniel Taliun; Matthias Thurner; Neil R Robertson; Jason M Torres; N William Rayner; Anthony J Payne; Valgerdur Steinthorsdottir; Robert A Scott; Niels Grarup; James P Cook; Ellen M Schmidt; Matthias Wuttke; Chloé Sarnowski; Reedik Mägi; Jana Nano; Christian Gieger; Stella Trompet; Cécile Lecoeur; Michael H Preuss; Bram Peter Prins; Xiuqing Guo; Lawrence F Bielak; Jennifer E Below; Donald W Bowden; John Campbell Chambers; Young Jin Kim; Maggie C Y Ng; Lauren E Petty; Xueling Sim; Weihua Zhang; Amanda J Bennett; Jette Bork-Jensen; Chad M Brummett; Mickaël Canouil; Kai-Uwe Ec Kardt; Krista Fischer; Sharon L R Kardia; Florian Kronenberg; Kristi Läll; Ching-Ti Liu; Adam E Locke; Jian'an Luan; Ioanna Ntalla; Vibe Nylander; Sebastian Schönherr; Claudia Schurmann; Loïc Yengo; Erwin P Bottinger; Ivan Brandslund; Cramer Christensen; George Dedoussis; Jose C Florez; Ian Ford; Oscar H Franco; Timothy M Frayling; Vilmantas Giedraitis; Sophie Hackinger; Andrew T Hattersley; Christian Herder; M Arfan Ikram; Martin Ingelsson; Marit E Jørgensen; Torben Jørgensen; Jennifer Kriebel; Johanna Kuusisto; Symen Ligthart; Cecilia M Lindgren; Allan Linneberg; Valeriya Lyssenko; Vasiliki Mamakou; Thomas Meitinger; Karen L Mohlke; Andrew D Morris; Girish Nadkarni; James S Pankow; Annette Peters; Naveed Sattar; Alena Stančáková; Konstantin Strauch; Kent D Taylor; Barbara Thorand; Gudmar Thorleifsson; Unnur Thorsteinsdottir; Jaakko Tuomilehto; Daniel R Witte; Josée Dupuis; Patricia A Peyser; Eleftheria Zeggini; Ruth J F Loos; Philippe Froguel; Erik Ingelsson; Lars Lind; Leif Groop; Markku Laakso; Francis S Collins; J Wouter Jukema; Colin N A Palmer; Harald Grallert; Andres Metspalu; Abbas Dehghan; Anna Köttgen; Goncalo R Abecasis; James B Meigs; Jerome I Rotter; Jonathan Marchini; Oluf Pedersen; Torben Hansen; Claudia Langenberg; Nicholas J Wareham; Kari Stefansson; Anna L Gloyn; Andrew P Morris; Michael Boehnke; Mark I McCarthy

doi:10.1038/s41588-018-0241-6

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Fine-mapping type 2 diabetes loci to single-variant resolution using high-density imputation and islet-specific epigenome maps

Journal article

Peer reviewed

Fine-mapping type 2 diabetes loci to single-variant resolution using high-density imputation and islet-specific epigenome maps

Anubha Mahajan, Daniel Taliun, Matthias Thurner, Neil R Robertson, Jason M Torres, N William Rayner, Anthony J Payne, Valgerdur Steinthorsdottir, Robert A Scott, Niels Grarup, …

Nature genetics, Vol.50(11), pp.1505-+

01/11/2018

DOI: https://doi.org/10.1038/s41588-018-0241-6

PMID: 30297969

Abstract

Body Mass Index

Case-Control Studies

Chromosome Mapping - methods

Diabetes Mellitus, Type 2 - epidemiology

Diabetes Mellitus, Type 2 - genetics

Diabetes Mellitus, Type 2 - pathology

Epigenesis, Genetic

Female

Gene Frequency

Genetic Loci - genetics

Genetic Predisposition to Disease

Genome, Human - genetics

Genome-Wide Association Study

High-Throughput Screening Assays - methods

Humans

Islets of Langerhans - metabolism

Islets of Langerhans - pathology

Linkage Disequilibrium

Male

Meta-Analysis as Topic

Polymorphism, Single Nucleotide

Sex Factors

White People - genetics

We expanded GWAS discovery for type 2 diabetes (T2D) by combining data from 898,130 European-descent individuals (9% cases), after imputation to high-density reference panels. With these data, we (i) extend the inventory of T2D-risk variants (243 loci, 135 newly implicated in T2D predisposition, comprising 403 distinct association signals); (ii) enrich discovery of lower-frequency risk alleles (80 index variants with minor allele frequency <5%, 14 with estimated allelic odds ratio >2); (iii) substantially improve fine-mapping of causal variants (at 51 signals, one variant accounted for >80% posterior probability of association (PPA)); (iv) extend fine-mapping through integration of tissue-specific epigenomic information (islet regulatory annotations extend the number of variants with PPA >80% to 73); (v) highlight validated therapeutic targets (18 genes with associations attributable to coding variants); and (vi) demonstrate enhanced potential for clinical translation (genome-wide chip heritability explains 18% of T2D risk; individuals in the extremes of a T2D polygenic risk score differ more than ninefold in prevalence).

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Title: Fine-mapping type 2 diabetes loci to single-variant resolution using high-density imputation and islet-specific epigenome maps
Creators - without role: Anubha Mahajan - Oxford Centre for Diabetes, Endocrinology and Metabolism
Daniel Taliun - Statistical Research
Matthias Thurner - Oxford Centre for Diabetes, Endocrinology and Metabolism
Neil R Robertson - Wellcome Centre for Human Genetics
Jason M Torres - University of Oxford
N William Rayner - Wellcome Sanger Institute
Anthony J Payne - University of Oxford
Valgerdur Steinthorsdottir - deCODE Genetics
Robert A Scott - University of Cambridge
Niels Grarup - Novo Nordisk Foundation
James P Cook - University of Liverpool
Ellen M Schmidt - University of Michigan–Ann Arbor
Matthias Wuttke - University of Freiburg
Chloé Sarnowski - Boston University
Reedik Mägi - University of Tartu
Jana Nano - Erasmus MC
Christian Gieger - German Center for Diabetes Research
Stella Trompet - Leiden University Medical Center
Cécile Lecoeur - Pasteur Institute of Lille
Michael H Preuss - Icahn School of Medicine at Mount Sinai
Bram Peter Prins - Wellcome Sanger Institute
Xiuqing Guo - The Lundquist Institute
Lawrence F Bielak - University of Michigan–Ann Arbor
Jennifer E Below - Vanderbilt University Medical Center
Donald W Bowden - Wake Forest University
John Campbell Chambers - Nanyang Technological University
Young Jin Kim - Division of Genome Research, Center for Genome Science, Korea National Institute of Health, Chungcheongbuk-do, Republic of Korea
Maggie C Y Ng - Wake Forest University
Lauren E Petty - Vanderbilt University Medical Center
Xueling Sim - National University of Singapore
Weihua Zhang - Imperial College London
Amanda J Bennett - University of Oxford
Jette Bork-Jensen - Novo Nordisk Foundation
Chad M Brummett - University of Michigan–Ann Arbor
Mickaël Canouil - Pasteur Institute of Lille
Kai-Uwe Ec Kardt - Charité - Universitätsmedizin Berlin
Krista Fischer - University of Tartu
Sharon L R Kardia - University of Michigan–Ann Arbor
Florian Kronenberg - Innsbruck Medical University
Kristi Läll - University of Tartu
Ching-Ti Liu - Boston University
Adam E Locke - James S. McDonnell Foundation
Jian'an Luan - MRC Epidemiology Unit
Ioanna Ntalla - Queen Mary University of London
Vibe Nylander - Oxford Centre for Diabetes, Endocrinology and Metabolism
Sebastian Schönherr - Innsbruck Medical University
Claudia Schurmann - Icahn School of Medicine at Mount Sinai
Loïc Yengo - Pasteur Institute of Lille
Erwin P Bottinger - Icahn School of Medicine at Mount Sinai
Ivan Brandslund - University of Southern Denmark
Cramer Christensen - Lillebaelt Hospital
George Dedoussis - Harokopio University of Athens
Jose C Florez - Broad Institute
Ian Ford - University of Glasgow
Oscar H Franco - Erasmus MC
Timothy M Frayling - University of Exeter
Vilmantas Giedraitis - Uppsala University
Sophie Hackinger - Wellcome Sanger Institute
Andrew T Hattersley - University of Exeter
Christian Herder - Deutsches Diabetes-Zentrum e.V.
M Arfan Ikram - Erasmus MC
Martin Ingelsson - Uppsala University
Marit E Jørgensen - Steno Diabetes Center
Torben Jørgensen - University of Copenhagen
Jennifer Kriebel - Helmholtz Zentrum München
Johanna Kuusisto - Kuopio University Hospital
Symen Ligthart - Erasmus MC
Cecilia M Lindgren - University of Oxford
Allan Linneberg - University of Copenhagen
Valeriya Lyssenko - Lund University
Vasiliki Mamakou - National and Kapodistrian University of Athens
Thomas Meitinger - German Centre for Cardiovascular Research
Karen L Mohlke - University of North Carolina at Chapel Hill
Andrew D Morris - University of Edinburgh
Girish Nadkarni - Icahn School of Medicine at Mount Sinai
James S Pankow - University of Minnesota
Annette Peters - Helmholtz Zentrum München
Naveed Sattar - University of Glasgow
Alena Stančáková - University of Eastern Finland
Konstantin Strauch - Zimmer Biomet
Kent D Taylor - Ronald Reagan UCLA Medical Center
Barbara Thorand - Helmholtz Zentrum München
Gudmar Thorleifsson - deCODE Genetics
Unnur Thorsteinsdottir - deCODE Genetics
Jaakko Tuomilehto - King Abdulaziz University
Daniel R Witte - Danish Diabetes Academy
Josée Dupuis - National Heart Lung and Blood Institute
Patricia A Peyser - University of Michigan–Ann Arbor
Eleftheria Zeggini - Wellcome Sanger Institute
Ruth J F Loos - Icahn School of Medicine at Mount Sinai
Philippe Froguel - Pasteur Institute of Lille
Erik Ingelsson - Stanford University
Lars Lind - Uppsala University
Leif Groop - University of Helsinki
Markku Laakso - Kuopio University Hospital
Francis S Collins - National Institutes of Health
J Wouter Jukema - Leiden University Medical Center
Colin N A Palmer - Ninewells Hospital
Harald Grallert - Helmholtz Zentrum München
Andres Metspalu - University of Tartu
Abbas Dehghan - Imperial College London
Anna Köttgen - University of Freiburg
Goncalo R Abecasis - University of Michigan–Ann Arbor
James B Meigs - Massachusetts General Hospital
Jerome I Rotter - Harbor–UCLA Medical Center
Jonathan Marchini - University of Oxford
Oluf Pedersen - University of Copenhagen
Torben Hansen - University of Southern Denmark
Claudia Langenberg - University of Cambridge
Nicholas J Wareham - University of Cambridge
Kari Stefansson - University of Iceland
Anna L Gloyn - University of Oxford
Andrew P Morris - Ninewells Hospital
Michael Boehnke - University of Michigan–Ann Arbor
Mark I McCarthy - University of Oxford
Publication Details: Nature genetics, Vol.50(11), pp.1505-+
Grant note: R01 DK066358 / NIDDK NIH HHS K24 DK080140 / NIDDK NIH HHS U01 DK105556 / NIDDK NIH HHS U01 DK078616 / NIDDK NIH HHS P30 DK116074 / NIDDK NIH HHS MC_UU_12015/1 / Medical Research Council R01 DK072193 / NIDDK NIH HHS R01 DK093757 / NIDDK NIH HHS U01 DK105535 / NIDDK NIH HHS 200837/Z/16/Z / Wellcome Trust R01 HL105756 / NHLBI NIH HHS R01 DK087914 / NIDDK NIH HHS U01 DK062370 / NIDDK NIH HHS R01 HL119443 / NHLBI NIH HHS P30 DK020572 / NIDDK NIH HHS 098381 / Wellcome Trust K99 AG066849 / NIA NIH HHS G0601261 / Medical Research Council R01 DK078616 / NIDDK NIH HHS
Identifiers: 9937116608331
Academic Unit: King Abdulaziz University
Language: English
Resource Type: Journal article