RT Journal Article
SR Electronic
T1 Refining the accuracy of validated target identification through coding variant fine-mapping in type 2 diabetes
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 144410
DO 10.1101/144410
A1 Anubha Mahajan
A1 Jennifer Wessel
A1 Sara M Willems
A1 Wei Zhao
A1 Neil R Robertson
A1 Audrey Y Chu
A1 Wei Gan
A1 Hidetoshi Kitajima
A1 Daniel Taliun
A1 N William Rayner
A1 Xiuqing Guo
A1 Yingchang Lu
A1 Man Li
A1 Richard A Jensen
A1 Yao Hu
A1 Shaofeng Huo
A1 Kurt K Lohman
A1 Weihua Zhang
A1 James P Cook
A1 Bram Prins
A1 Jason Flannick
A1 Niels Grarup
A1 Vassily Vladimirovich Trubetskoy
A1 Jasmina Kravic
A1 Young Jin Kim
A1 Denis V Rybin
A1 Hanieh Yaghootkar
A1 Martina Müller-Nurasyid
A1 Karina Meidtner
A1 Ruifang Li-Gao
A1 Tibor V Varga
A1 Jonathan Marten
A1 Jin Li
A1 Albert Vernon Smith
A1 Ping An
A1 Symen Ligthart
A1 Stefan Gustafsson
A1 Giovanni Malerba
A1 Ayse Demirkan
A1 Juan Fernandez Tajes
A1 Valgerdur Steinthorsdottir
A1 Matthias Wuttke
A1 Cécile Lecoeur
A1 Michael Preuss
A1 Lawrence F Bielak
A1 Marielisa Graff
A1 Heather M Highland
A1 Anne E Justice
A1 Dajiang J Liu
A1 Eirini Marouli
A1 Gina Marie Peloso
A1 Helen R Warren
A1 ExomeBP Consortium
A1 MAGIC Consortium
A1 GIANT consortium
A1 Saima Afaq
A1 Shoaib Afzal
A1 Emma Ahlqvist
A1 Peter Almgren
A1 Najaf Amin
A1 Lia B Bang
A1 Alain G Bertoni
A1 Cristina Bombieri
A1 Jette Bork-Jensen
A1 Ivan Brandslund
A1 Jennifer A Brody
A1 Noël P Burtt
A1 Mickaёl Canouil
A1 Yii-Der Ida Chen
A1 Yoon Shin Cho
A1 Cramer Christensen
A1 Sophie V Eastwood
A1 Kai-Uwe Eckardt
A1 Krista Fischer
A1 Giovanni Gambaro
A1 Vilmantas Giedraitis
A1 Megan L Grove
A1 Hugoline G de Haan
A1 Sophie Hackinger
A1 Yang Hai
A1 Sohee Han
A1 Anne Tybjærg-Hansen
A1 Marie-France Hivert
A1 Bo Isomaa
A1 Susanne Jäger
A1 Marit E Jørgensen
A1 Torben Jørgensen
A1 Annemari Käräjämäki
A1 Bong-Jo Kim
A1 Sung Soo Kim
A1 Heikki A Koistinen
A1 Peter Kovacs
A1 Jennifer Kriebel
A1 Florian Kronenberg
A1 Kristi Läll
A1 Leslie A Lange
A1 Jung-Jin Lee
A1 Benjamin Lehne
A1 Huaixing Li
A1 Keng-Hung Lin
A1 Allan Linneberg
A1 Ching-Ti Liu
A1 Jun Liu
A1 Marie Loh
A1 Reedik Mägi
A1 Vasiliki Mamakou
A1 Roberta McKean-Cowdin
A1 Girish Nadkarni
A1 Matt Neville
A1 Sune F Nielsen
A1 Ioanna Ntalla
A1 Patricia A Peyser
A1 Wolfgang Rathmann
A1 Kenneth Rice
A1 Stephen S Rich
A1 Line Rode
A1 Olov Rolandsson
A1 Sebastian Schönherr
A1 Elizabeth Selvin
A1 Kerrin S Small
A1 Alena Stančáková
A1 Praveen Surendran
A1 Kent D Taylor
A1 Tanya M Teslovich
A1 Barbara Thorand
A1 Gudmar Thorleifsson
A1 Adrienne Tin
A1 Anke Tönjes
A1 Anette Varbo
A1 Daniel R Witte
A1 Andrew R Wood
A1 Pranav Yajnik
A1 Jie Yao
A1 Loïc Yengo
A1 Robin Young
A1 Philippe Amouyel
A1 Heiner Boeing
A1 Eric Boerwinkle
A1 Erwin P Bottinger
A1 Rajiv Chowdhury
A1 Francis S Collins
A1 George Dedoussis
A1 Abbas Dehghan
A1 Panos Deloukas
A1 Marco M Ferrario
A1 Jean Ferrières
A1 Jose C Florez
A1 Philippe Frossard
A1 Vilmundur Gudnason
A1 Tamara B Harris
A1 Susan R Heckbert
A1 Joanna M M Howson
A1 Martin Ingelsson
A1 Sekar Kathiresan
A1 Frank Kee
A1 Johanna Kuusisto
A1 Claudia Langenberg
A1 Lenore J Launer
A1 Cecilia M Lindgren
A1 Satu Männistö
A1 Thomas Meitinger
A1 Olle Melander
A1 Karen L Mohlke
A1 Marie Moitry
A1 Andrew D Morris
A1 Alison D Murray
A1 Renée de Mutsert
A1 Marju Orho-Melander
A1 Katharine R Owen
A1 Markus Perola
A1 Annette Peters
A1 Michael A Province
A1 Asif Rasheed
A1 Paul M Ridker
A1 Fernando Rivadineira
A1 Frits R Rosendaal
A1 Anders H Rosengren
A1 Veikko Salomaa
A1 Wayne H -H Sheu
A1 Rob Sladek
A1 Blair H Smith
A1 Konstantin Strauch
A1 André G Uitterlinden
A1 Rohit Varma
A1 Cristen J Willer
A1 Matthias Blüher
A1 Adam S Butterworth
A1 John Campbell Chambers
A1 Daniel I Chasman
A1 John Danesh
A1 Cornelia van Duijn
A1 Josee Dupuis
A1 Oscar H Franco
A1 Paul W Franks
A1 Philippe Froguel
A1 Harald Grallert
A1 Leif Groop
A1 Bok-Ghee Han
A1 Torben Hansen
A1 Andrew T Hattersley
A1 Caroline Hayward
A1 Erik Ingelsson
A1 Sharon LR Kardia
A1 Fredrik Karpe
A1 Jaspal Singh Kooner
A1 Anna Köttgen
A1 Kari Kuulasmaa
A1 Markku Laakso
A1 Xu Lin
A1 Lars Lind
A1 Yongmei Liu
A1 Ruth J F Loos
A1 Jonathan Marchini
A1 Andres Metspalu
A1 Dennis Mook-Kanamori
A1 Børge G Nordestgaard
A1 Colin N A Palmer
A1 James S Pankow
A1 Oluf Pedersen
A1 Bruce M Psaty
A1 Rainer Rauramaa
A1 Naveed Sattar
A1 Matthias B Schulze
A1 Nicole Soranzo
A1 Timothy D Spector
A1 Kari Stefansson
A1 Michael Stumvoll
A1 Unnur Thorsteinsdottir
A1 Tiinamaija Tuomi
A1 Jaakko Tuomilehto
A1 Nicholas J Wareham
A1 James G Wilson
A1 Eleftheria Zeggini
A1 Robert A Scott
A1 Inês Barroso
A1 Timothy M Frayling
A1 Mark O Goodarzi
A1 James B Meigs
A1 Michael Boehnke
A1 Danish Saleheen
A1 Andrew P Morris
A1 Jerome I Rotter
A1 Mark I McCarthy
YR 2017
UL http://biorxiv.org/content/early/2017/05/31/144410.1.abstract
AB Identification of coding variant associations for complex diseases offers a direct route to biological insight, but is dependent on appropriate inference concerning the causal impact of those variants on disease risk. We aggregated exome-array and exome sequencing data for 81,412 type 2 diabetes (T2D) cases and 370,832 controls of diverse ancestry, identifying 40 distinct coding variant association signals (at 38 loci) reaching significance (p<2.2×10-7). Of these, 16 represent novel associations mapping outside known genome-wide association study (GWAS) signals. We make two important observations. First, despite a threefold increase in sample size over previous efforts, only five of the 40 signals are driven by variants with minor allele frequency <5%, and we find no evidence for low-frequency variants with allelic odds ratio >1.36. Second, we used GWAS data from 50,160 T2D cases and 465,272 controls to fine-map associated coding variants in their regional context, with and without additional weighting, to account for the global enrichment of complex trait association signals in coding exons. We demonstrate convincing support (posterior probability >80% under the “annotation-weighted” model) that coding variants are causal for the association at 16 of the 40 signals (including novel signals involving POC5 p.His36Arg, ANKH p.Arg187Gln, WSCD2 p.Thr113Ile, PLCB3 p.Ser778Leu, and PNPLA3 p.Ile148Met). However, one third of coding variant association signals represent “false leads” at which naïve analysis would have led to an erroneous inference regarding the effector transcript mediating the signal. Accurate identification of validated targets is dependent on correct specification of the contribution of coding and non-coding mediated mechanisms at associated loci.