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

Authors:
Dr Anubha Mahajan, PhD
Dr Anubha Mahajan, PhD
Wellcome Trust Centre for Human Genetics, University of Oxford
UK
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

Nat Genet 2018 11 8;50(11):1505-1513. Epub 2018 Oct 8.

Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, UK.

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).

Download full-text PDF

Source
http://www.nature.com/articles/s41588-018-0241-6
Publisher Site
http://dx.doi.org/10.1038/s41588-018-0241-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6287706PMC
November 2018
66 Reads
2 Citations
29.352 Impact Factor

Publication Analysis

Top Keywords

type diabetes
8
variants
5
translation genome-wide
4
discovery lower-frequency
4
enrich discovery
4
signals enrich
4
association signals
4
number variants
4
lower-frequency risk
4
risk alleles
4
variants minor
4
genes associations
4
clinical translation
4
alleles variants
4
distinct association
4
extend number
4
genome-wide chip
4
newly implicated
4
implicated t2d
4
heritability explains
4

References

(Supplied by CrossRef)

RA Scott et al.
Diabetes 2017

W Zhao et al.
Nat. Genet. 2017

A Mahajan et al.
Nat. Genet. 2018

S McCarthy et al.
Nat. Genet. 2016

H Jónsson et al.
Sci. Data 2017

J Flannick et al.
Nat. Rev. Genet. 2016

BF Voight et al.
Nat. Genet. 2010

AP Morris et al.
Nat. Genet. 2012

JS Kooner et al.
Nat. Genet. 2011

YS Cho et al.
Nat. Genet. 2011

LA Lotta et al.
Nat. Genet. 2017

Similar Publications