| Title: | Fine-mapping type 2 diabetes loci to single-variant resolution using high-density imputation and islet-specific epigenome maps |
| Journal: | Nature Genetics |
| Published: | 8 Oct 2018 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/30297969/ |
| DOI: | https://doi.org/10.1038/s41588-018-0241-6 |
| URL: | https://europepmc.org/articles/pmc6287706?pdf=render |
Publication 8572
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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).</p>
115 Authors
- 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
1 Application
| Application ID | Title |
|---|---|
| 9161 | Type 2 diabetes: using genetic discovery to drive biological inference and translational opportunities. |
Enabling scientific discoveries that improve human health