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

Nat Genet
Authors
Anubha Mahajan
Daniel Taliun
Matthias Thurner
Neil Robertson
Jason Torres
N William Rayner
Anthony Payne
Valgerdur Steinthorsdottir
Robert Scott
Niels Grarup
James Cook
Ellen Schmidt
Matthias Wuttke
Chloe Sarnowski
Reedik Mägi
Jana Nano
Christian Gieger
Stella Trompet
Cecile Lecoeur
Michael Preuss
Bram Prins
Xiuqing Guo
Lawrence Bielak
Jennifer Below
Donald Bowden
John Chambers
Young Kim
Maggie C Y Ng
Lauren Petty
Xueling Sim
Weihua Zhang
Amanda Bennett
Jette Bork-Jensen
Chad Brummett
Mickaël Canouil
Kai-Uwe Kardt
Krista Fischer
Sharon Kardia
Florian Kronenberg
Kristi Läll
Ching-Ti Liu
Adam Locke
Jian'an Luan
Ioanna Ntalla
Vibe Nylander
Sebastian Schönherr
Claudia Schurmann
Loic Yengo
Erwin Bottinger
Ivan Brandslund
Cramer Christensen
George Dedoussis
Jose Florez
Ian Ford
Oscar Franco
Timothy Frayling
Vilmantas Giedraitis
Sophie Hackinger
Andrew Hattersley
Christian Herder
M Arfan Ikram
Martin Ingelsson
Marit Jørgensen
Torben Jørgensen
Jennifer Kriebel
Johanna Kuusisto
Symen Ligthart
Cecilia Lindgren
Allan Linneberg
Valeriya Lyssenko
Vasiliki Mamakou
Thomas Meitinger
Karen Mohlke
Andrew Morris
Girish Nadkarni
James Pankow
Annette Peters
Naveed Sattar
Alena Stančáková
Konstantin Strauch
Kent Taylor
Barbara Thorand
Gudmar Thorleifsson
Unnur Thorsteinsdottir
Jaakko Tuomilehto
Daniel Witte
Josée Dupuis
Patricia Peyser
Eleftheria Zeggini
Ruth Loos
Philippe Froguel
Erik Ingelsson
Lars Lind
Leif Groop
Markku Laakso
Francis Collins
J Wouter Jukema
Colin Palmer
Harald Grallert
Andres Metspalu
Abbas Dehghan
Anna Köttgen
Gonçalo Abecasis
James Meigs
Jerome Rotter
Jonathan Marchini
Oluf Pedersen
Torben Hansen
Claudia Langenberg
Nicholas Wareham
Kari Stefansson
Anna Gloyn
Andrew Morris
Michael Boehnke
Mark McCarthy
Keywords
Female
Humans
Male
Genetic Predisposition to Disease
Chromosome Mapping
Gene Frequency
Genome-Wide Association Study
Polymorphism, Single Nucleotide
Linkage Disequilibrium
Case-Control Studies
Epigenesis, Genetic
Genome, Human
Genetic Loci
Diabetes Mellitus, Type 2
Body Mass Index
Sex Factors
High-Throughput Screening Assays
Islets of Langerhans
Meta-Analysis as Topic
Whites
Abstract

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).
Year of Publication
2018
Journal
Nat Genet
Volume
50
Issue
11
Pages
1505-1513
Date Published
2018 11
ISSN
1546-1718
DOI
10.1038/s41588-018-0241-6
PubMed ID
30297969
PubMed Central ID
PMC6287706
Links
Grant list
U01 DK105556 / DK / NIDDK NIH HHS / United States
MC_UU_12015/1 / MRC_ / Medical Research Council / United Kingdom
R01 DK072193 / DK / NIDDK NIH HHS / United States
R01 DK066358 / DK / NIDDK NIH HHS / United States
K24 DK080140 / DK / NIDDK NIH HHS / United States
U01 DK078616 / DK / NIDDK NIH HHS / United States
U01 DK062370 / DK / NIDDK NIH HHS / United States
G0601261 / MRC_ / Medical Research Council / United Kingdom
P30 DK020572 / DK / NIDDK NIH HHS / United States
P30 DK116074 / DK / NIDDK NIH HHS / United States
098381 / WT_ / Wellcome Trust / United Kingdom
R01 DK093757 / DK / NIDDK NIH HHS / United States
R01 DK078616 / DK / NIDDK NIH HHS / United States
R01 HL119443 / HL / NHLBI NIH HHS / United States
R01 HL105756 / HL / NHLBI NIH HHS / United States
R01 DK087914 / DK / NIDDK NIH HHS / United States
U01 DK105535 / DK / NIDDK NIH HHS / United States

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