Refining the accuracy of validated target identification through coding variant fine-mapping in type 2 diabetes
Authors: Mahajan Anubha , Wessel Jennifer , Willems Sara M , Zhao Wei , Robertson Neil R , Chu Audrey Y , Gan Wei , Kitajima Hidetoshi , Taliun Daniel , Rayner N William , Guo Xiuqing , Lu Yingchang , Li Man , Jensen Richard A , Hu Yao , Huo Shaofeng , Lohman Kurt K , Zhang Weihua , Cook James P , Prins Bram , Flannick Jason , Grarup Niels , Trubetskoy Vassily Vladimirovich , Kravic Jasmina , Kim Young Jin , Rybin Denis V , Yaghootkar Hanieh , Mñller-Nurasyid Martina , Meidtner Karina , Li-Gao Ruifang , Varga Tibor V , Marten Jonathan , Li Jin , Smith Albert Vernon , An Ping , Ligthart Symen , Gustafsson Stefan , Malerba Giovanni , Demirkan Ayse , Tajes Juan Fernandez , Steinthorsdottir Valgerdur , Wuttke Matthias , Lecoeur Cécile , Preuss Michael , Bielak Lawrence F , Graff Marielisa , Highland Heather M , Justice Anne E , Liu Dajiang J , Marouli Eirini , Peloso Gina Marie , Warren Helen R ,   ExomeBP Consortium,   MAGIC Consortium,   GIANT Consortium, Afaq Saima , Afzal Shoaib , Ahlqvist Emma , Almgren Peter , Amin Najaf , Bang Lia B , Bertoni Alain G , Bombieri Cristina , Bork-Jensen Jette , Brandslund Ivan , Brody Jennifer A , Burtt Noël P , Canouil Mickaël , Chen Yii-Der Ida , Cho Yoon Shin , Christensen Cramer , Eastwood Sophie V , Eckardt Kai-Uwe , Fischer Krista , Gambaro Giovanni , Giedraitis Vilmantas , Grove Megan L , de Haan Hugoline G , Hackinger Sophie , Hai Yang , Han Sohee , Tybjærg-Hansen Anne , Hivert Marie-France , Isomaa Bo , Jäger Susanne , Jørgensen Marit E , Jørgensen Torben , Käräjämäki Annemari , Kim Bong-Jo , Kim Sung Soo , Koistinen Heikki A , Kovacs Peter , Kriebel Jennifer , Kronenberg Florian , Läll Kristi , Lange Leslie A , Lee Jung-Jin , Lehne Benjamin , Li Huaixing , Lin Keng-Hung , Linneberg Allan , Liu Ching-Ti , Liu Jun , Loh Marie , Mägi Reedik , Mamakou Vasiliki , McKean-Cowdin Roberta , Nadkarni Girish , Neville Matt , Nielsen Sune F , Ntalla Ioanna , Peyser Patricia A , Rathmann Wolfgang , Rice Kenneth , Rich Stephen S , Rode Line , Rolandsson Olov , Schönherr Sebastian , Selvin Elizabeth , Small Kerrin S , Stančáková Alena , Surendran Praveen , Taylor Kent D , Teslovich Tanya M , Thorand Barbara , Thorleifsson Gudmar , Tin Adrienne , Tönjes Anke , Varbo Anette , Witte Daniel R , Wood Andrew R , Yajnik Pranav , Yao Jie , Yengo Loïc , Young Robin , Amouyel Philippe , Boeing Heiner , Boerwinkle Eric , Bottinger Erwin P , Chowdhury Rajiv , Collins Francis S , Dedoussis George , Dehghan Abbas , Deloukas Panos , Ferrario Marco M , Ferrières Jean , Florez Jose C , Frossard Philippe , Gudnason Vilmundur , Harris Tamara B , Heckbert Susan R , Howson Joanna M M , Ingelsson Martin , Kathiresan Sekar , Kee Frank , Kuusisto Johanna , Langenberg Claudia , Launer Lenore J , Lindgren Cecilia M , Männistö Satu , Meitinger Thomas , Melander Olle , Mohlke Karen L , Moitry Marie , Morris Andrew D , Murray Alison D , de Mutsert Renée , Orho-Melander Marju , Owen Katharine R , Perola Markus , Peters Annette , Province Michael A , Rasheed Asif , Ridker Paul M , Rivadineira Fernando , Rosendaal Frits R , Rosengren Anders H , Salomaa Veikko , Sheu Wayne H-H , Sladek Rob , Smith Blair H , Strauch Konstantin , Uitterlinden André G , Varma Rohit , Willer Cristen J , Blüher Matthias , Butterworth Adam S , Chambers John Campbell , Chasman Daniel I , Danesh John , Duijn Cornelia van , Dupuis Josee , Franco Oscar H , Franks Paul W , Froguel Philippe , Grallert Harald , Groop Leif , Han Bok-Ghee , Hansen Torben , Hattersley Andrew T , Hayward Caroline , Ingelsson Erik , Kardia Sharon LR , Karpe Fredrik , Kooner Jaspal Singh , Köttgen Anna , Kuulasmaa Kari , Laakso Markku , Lin Xu , Lind Lars , Liu Yongmei , Loos Ruth J F , Marchini Jonathan , Metspalu Andres , Mook-Kanamori Dennis , Nordestgaard Børge G , Palmer Colin N A , Pankow James S , Pedersen Oluf , Psaty Bruce M , Rauramaa Rainer , Sattar Naveed , Schulze Matthias B , Soranzo Nicole , Spector Timothy D , Stefansson Kari , Stumvoll Michael , Thorsteinsdottir Unnur , Tuomi Tiinamaija , Tuomilehto Jaakko , Wareham Nicholas J , Wilson James G , Zeggini Eleftheria , Scott Robert A , Barroso Inês , Frayling Timothy M , Goodarzi Mark O , Meigs James B , Boehnke Michael , Saleheen Danish , Morris Andrew P , Rotter Jerome I , McCarthy Mark I 
Published: June 2017

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 coding variant 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 >1.29. Second, we used GWAS data from 50,160 T2D cases and 465,272 controls of European ancestry to fine-map these 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. At the 37 signals for which we attempted fine-mapping, we demonstrate convincing support (posterior probability >80% under the “annotation-weighted” model) that coding variants are causal for the association at 16 (including novel signals involvingPOC5p.His36Arg,ANKHp.Arg187Gln,WSCD2p.Thr113Ile,PLCB3p.Ser778Leu, andPNPLA3p.Ile148Met). However, at 13 of the 37 loci, the associated coding variants represent “false leads” and naïve analysis could 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.