Refining the accuracy of validated target identification through coding variant fine-mapping in type 2 diabetes

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

doi:10.1038/s41588-018-0084-1

Refining the accuracy of validated target identification through coding variant fine-mapping in type 2 diabetes

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

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Abstract

We aggregated coding variant data for 81,412 type 2 diabetes cases and 370,832 controls of diverse ancestry, identifying 40 coding variant association signals (P < 2.2 × 10−7); of these, 16 map outside known risk-associated loci. We make two important observations. First, only five of these signals are driven by low-frequency variants: even for these, effect sizes are modest (odds ratio ≤1.29). Second, when we used large-scale genome-wide association data to fine-map the associated variants in their regional context, accounting for the global enrichment of complex trait associations in coding sequence, compelling evidence for coding variant causality was obtained for only 16 signals. At 13 others, the associated coding variants clearly represent ‘false leads’ with potential to generate erroneous mechanistic inference. Coding variant associations offer a direct route to biological insight for complex diseases and identification of validated therapeutic targets; however, appropriate mechanistic inference requires careful specification of their causal contribution to disease predisposition.

Original language	English
Pages (from-to)	559-571
Number of pages	13
Journal	Nature Genetics
Volume	50
Issue number	4
Early online date	9 Apr 2018
DOIs	https://doi.org/10.1038/s41588-018-0084-1
Publication status	Published - 30 Apr 2018

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Refining the accuracy of validated target identification through coding variant fine-mapping in type 2 diabetesAccepted author manuscript, 1.11 MBLicence: Other

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Mahajan, A., Wessel, J., Willems, S. M., Zhao, W., Robertson, N. R., Chu, A. Y., Gan, W., Kitajima, H., Taliun, D., Rayner, N. W., Guo, X., Lu, Y., Li, M., Jensen, R. A., Hu, Y., Huo, S., Lohman, K. K., Zhang, W., Cook, J. P., ... McCarthy, M. I. (2018). Refining the accuracy of validated target identification through coding variant fine-mapping in type 2 diabetes. Nature Genetics, 50(4), 559-571. https://doi.org/10.1038/s41588-018-0084-1

Mahajan, A, Wessel, J, Willems, SM, Zhao, W, Robertson, NR, Chu, AY, Gan, W, Kitajima, H, Taliun, D, Rayner, NW, Guo, X, Lu, Y, Li, M, Jensen, RA, Hu, Y, Huo, S, Lohman, KK, Zhang, W, Cook, JP, Prins, BP, Flannick, J, Grarup, N, Trubetskoy, VV, Kravic, J, Kim, YJ, Rybin, DV, Yaghootkar, H, Müller-Nurasyid, M, Meidtner, K, Li-Gao, R, Varga, TV, Marten, J, Li, J, Smith, AV, An, P, Ligthart, S, Gustafsson, S, Malerba, G, Demirkan, A, Tajes, JF, Steinthorsdottir, V, Wuttke, M, Lecoeur, C, Preuss, M, Bielak, LF, Graff, M, Highland, HM, Justice, AE, Liu, DJ, Marouli, E, Peloso, GM, Warren, HR, Afaq, S, Afzal, S, Ahlqvist, E, Almgren, P, Amin, N, Bang, LB, Bertoni, AG, Bombieri, C, Bork-Jensen, J, Brandslund, I, Brody, JA, Burtt, NP, Canouil, M, Chen, Y-DI, Cho, YS, Christensen, C, Eastwood, SV, Eckardt, K-U, Fischer, K, Gambaro, G, Giedraitis, V, Grove, ML, de Haan, HG, Hackinger, S, Hai, Y, Han, S, Tybjærg-Hansen, A, Hivert, M-F, Isomaa, B, Jäger, S, Jørgensen, ME, Jørgensen, T, Käräjämäki, A, Kim, B-J, Kim, SS, Koistinen, HA, Kovacs, P, Kriebel, J, Kronenberg, F, Läll, K, Lange, LA, Lee, J-J, Lehne, B, Li, H, Lin, K-H, Linneberg, A, Liu, C-T, Liu, J, Loh, M, Mägi, R, Mamakou, V, McKean-Cowdin, R, Nadkarni, G, Neville, M, Nielsen, SF, Ntalla, I, Peyser, PA, Rathmann, W, Rice, K, Rich, SS, Rode, L, Rolandsson, O, Schönherr, S, Selvin, E, Small, KS, Stančáková, A, Surendran, P, Taylor, KD, Teslovich, TM, Thorand, B, Thorleifsson, G, Tin, A, Tönjes, A, Varbo, A, Witte, DR, Wood, AR, Yajnik, P, Yao, J, Yengo, L, Young, R, Amouyel, P, Boeing, H, Boerwinkle, E, Bottinger, EP, Chowdhury, R, Collins, FS, Dedoussis, G, Dehghan, A, Deloukas, P, Ferrario, MM, Ferrières, J, Florez, JC, Frossard, P, Gudnason, V, Harris, TB, Heckbert, SR, Howson, JMM, Ingelsson, M, Kathiresan, S, Kee, F, Kuusisto, J, Langenberg, C, Launer, LJ, Lindgren, CM, Männistö, S, Meitinger, T, Melander, O, Mohlke, KL, Moitry, M, Morris, AD, Murray, AD, de Mutsert, R, Orho-Melander, M, Owen, KR, Perola, M, Peters, A, Province, MA, Rasheed, A, Ridker, PM, Rivadineira, F, Rosendaal, FR, Rosengren, AH, Salomaa, V, Sheu, WH-H, Sladek, R, Smith, BH, Strauch, K, Uitterlinden, AG, Varma, R, Willer, CJ, Blüher, M, Butterworth, AS, Chambers, JC, Chasman, DI, Danesh, J, van Duijn, C, Dupuis, J, Franco, OH, Franks, PW, Froguel, P, Grallert, H, Groop, L, Han, B-G, Hansen, T, Hattersley, AT, Hayward, C, Ingelsson, E, Kardia, SLR, Karpe, F, Kooner, JS, Köttgen, A, Kuulasmaa, K, Laakso, M, Lin, X, Lind, L, Liu, Y, Loos, RJF, Marchini, J, Metspalu, A, Mook-Kanamori, D, Nordestgaard, BG, Palmer, CNA, Pankow, JS, Pedersen, O, Psaty, BM, Rauramaa, R, Sattar, N, Schulze, MB, Soranzo, N, Spector, TD, Stefansson, K, Stumvoll, M, Thorsteinsdottir, U, Tuomi, T, Tuomilehto, J, Wareham, NJ, Wilson, JG, Zeggini, E, Scott, RA, Barroso, I, Frayling, TM, Goodarzi, MO, Meigs, JB, Boehnke, M, Saleheen, D, Morris, AP, Rotter, JI & McCarthy, MI 2018, 'Refining the accuracy of validated target identification through coding variant fine-mapping in type 2 diabetes', Nature Genetics, vol. 50, no. 4, pp. 559-571. https://doi.org/10.1038/s41588-018-0084-1

@article{49472eb435ab4c9c99a832cb4eb842cc,

title = "Refining the accuracy of validated target identification through coding variant fine-mapping in type 2 diabetes",

abstract = "We aggregated coding variant data for 81,412 type 2 diabetes cases and 370,832 controls of diverse ancestry, identifying 40 coding variant association signals (P < 2.2 × 10−7); of these, 16 map outside known risk-associated loci. We make two important observations. First, only five of these signals are driven by low-frequency variants: even for these, effect sizes are modest (odds ratio ≤1.29). Second, when we used large-scale genome-wide association data to fine-map the associated variants in their regional context, accounting for the global enrichment of complex trait associations in coding sequence, compelling evidence for coding variant causality was obtained for only 16 signals. At 13 others, the associated coding variants clearly represent {\textquoteleft}false leads{\textquoteright} with potential to generate erroneous mechanistic inference. Coding variant associations offer a direct route to biological insight for complex diseases and identification of validated therapeutic targets; however, appropriate mechanistic inference requires careful specification of their causal contribution to disease predisposition.",

author = "Anubha Mahajan and Jennifer Wessel and Willems, {Sara M.} and Wei Zhao and Robertson, {Neil R.} and Chu, {Audrey Y.} and Wei Gan and Hidetoshi Kitajima and Daniel Taliun and Rayner, {N. William} and Xiuqing Guo and Yingchang Lu and Man Li and Jensen, {Richard A.} and Yao Hu and Shaofeng Huo and Lohman, {Kurt K.} and Weihua Zhang and Cook, {James P.} and Prins, {Bram Peter} and Jason Flannick and Niels Grarup and Trubetskoy, {Vassily Vladimirovich} and Jasmina Kravic and Kim, {Young Jin} and Rybin, {Denis V.} and Hanieh Yaghootkar and Martina M{\"u}ller-Nurasyid and Karina Meidtner and Ruifang Li-Gao and Varga, {Tibor V.} and Jonathan Marten and Jin Li and Smith, {Albert Vernon} and Ping An and Symen Ligthart and Stefan Gustafsson and Giovanni Malerba and Ayse Demirkan and Tajes, {Juan Fernandez} and Valgerdur Steinthorsdottir and Matthias Wuttke and C{\'e}cile Lecoeur and Michael Preuss and Bielak, {Lawrence F.} and Marielisa Graff and Highland, {Heather M.} and Justice, {Anne E.} and Liu, {Dajiang J.} and Eirini Marouli and Peloso, {Gina Marie} and Warren, {Helen R.} and Saima Afaq and Shoaib Afzal and Emma Ahlqvist and Peter Almgren and Najaf Amin and Bang, {Lia B.} and Bertoni, {Alain G.} and Cristina Bombieri and Jette Bork-Jensen and Ivan Brandslund and Brody, {Jennifer A.} and Burtt, {No{\"e}l P.} and Micka{\"e}l Canouil and Chen, {Yii-Der Ida} and Cho, {Yoon Shin} and Cramer Christensen and Eastwood, {Sophie V.} and Kai-Uwe Eckardt and Krista Fischer and Giovanni Gambaro and Vilmantas Giedraitis and Grove, {Megan L.} and {de Haan}, {Hugoline G.} and Sophie Hackinger and Yang Hai and Sohee Han and Anne Tybj{\ae}rg-Hansen and Marie-France Hivert and Bo Isomaa and Susanne J{\"a}ger and J{\o}rgensen, {Marit E.} and Torben J{\o}rgensen and Annemari K{\"a}r{\"a}j{\"a}m{\"a}ki and Bong-Jo Kim and Kim, {Sung Soo} and Koistinen, {Heikki A.} and Peter Kovacs and Jennifer Kriebel and Florian Kronenberg and Kristi L{\"a}ll and Lange, {Leslie A.} and Jung-Jin Lee and Benjamin Lehne and Huaixing Li and Keng-Hung Lin and Allan Linneberg and Ching-Ti Liu and Jun Liu and Marie Loh and Reedik M{\"a}gi and Vasiliki Mamakou and Roberta McKean-Cowdin and Girish Nadkarni and Matt Neville and Nielsen, {Sune F.} and Ioanna Ntalla and Peyser, {Patricia A.} and Wolfgang Rathmann and Kenneth Rice and Rich, {Stephen S.} and Line Rode and Olov Rolandsson and Sebastian Sch{\"o}nherr and Elizabeth Selvin and Small, {Kerrin S.} and Alena Stan{\v c}{\'a}kov{\'a} and Praveen Surendran and Taylor, {Kent D.} and Teslovich, {Tanya M.} and Barbara Thorand and Gudmar Thorleifsson and Adrienne Tin and Anke T{\"o}njes and Anette Varbo and Witte, {Daniel R.} and Wood, {Andrew R.} and Pranav Yajnik and Jie Yao and Lo{\"i}c Yengo and Robin Young and Philippe Amouyel and Heiner Boeing and Eric Boerwinkle and Bottinger, {Erwin P.} and Rajiv Chowdhury and Collins, {Francis S.} and George Dedoussis and Abbas Dehghan and Panos Deloukas and Ferrario, {Marco M.} and Jean Ferri{\`e}res and Florez, {Jose C.} and Philippe Frossard and Vilmundur Gudnason and Harris, {Tamara B.} and Heckbert, {Susan R.} and Howson, {Joanna M. M.} and Martin Ingelsson and Sekar Kathiresan and Frank Kee and Johanna Kuusisto and Claudia Langenberg and Launer, {Lenore J.} and Lindgren, {Cecilia M.} and Satu M{\"a}nnist{\"o} and Thomas Meitinger and Olle Melander and Mohlke, {Karen L.} and Marie Moitry and Morris, {Andrew D.} and Murray, {Alison D.} and {de Mutsert}, Ren{\'e}e and Marju Orho-Melander and Owen, {Katharine R.} and Markus Perola and Annette Peters and Province, {Michael A.} and Asif Rasheed and Ridker, {Paul M.} and Fernando Rivadineira and Rosendaal, {Frits R.} and Rosengren, {Anders H.} and Veikko Salomaa and Sheu, {Wayne H.-H.} and Rob Sladek and Smith, {Blair H.} and Konstantin Strauch and Uitterlinden, {Andr{\'e} G.} and Rohit Varma and Willer, {Cristen J.} and Matthias Bl{\"u}her and Butterworth, {Adam S.} and Chambers, {John Campbell} and Chasman, {Daniel I.} and John Danesh and {van Duijn}, Cornelia and Jos{\'e}e Dupuis and Franco, {Oscar H.} and Franks, {Paul W.} and Philippe Froguel and Harald Grallert and Leif Groop and Bok-Ghee Han and Torben Hansen and Hattersley, {Andrew T.} and Caroline Hayward and Erik Ingelsson and Kardia, {Sharon L. R.} and Fredrik Karpe and Kooner, {Jaspal Singh} and Anna K{\"o}ttgen and Kari Kuulasmaa and Markku Laakso and Xu Lin and Lars Lind and Yongmei Liu and Loos, {Ruth J. F.} and Jonathan Marchini and Andres Metspalu and Dennis Mook-Kanamori and Nordestgaard, {B{\o}rge G.} and Palmer, {Colin N. A.} and Pankow, {James S.} and Oluf Pedersen and Psaty, {Bruce M.} and Rainer Rauramaa and Naveed Sattar and Schulze, {Matthias B.} and Nicole Soranzo and Spector, {Timothy D.} and Kari Stefansson and Michael Stumvoll and Unnur Thorsteinsdottir and Tiinamaija Tuomi and Jaakko Tuomilehto and Wareham, {Nicholas J.} and Wilson, {James G.} and Eleftheria Zeggini and Scott, {Robert A.} and In{\^e}s Barroso and Frayling, {Timothy M.} and Goodarzi, {Mark O.} and Meigs, {James B.} and Michael Boehnke and Danish Saleheen and Morris, {Andrew P.} and Rotter, {Jerome I.} and McCarthy, {Mark I.}",

note = "Supplementary information is available for this paper at https://doi.org/10.1038/ s41588-018-0084-1. Acknowledgements A full list of acknowledgments appears in the Supplementary Note. Part of this work was conducted using the UK Biobank Resource under application number 9161.",

year = "2018",

month = apr,

day = "30",

doi = "10.1038/s41588-018-0084-1",

language = "English",

volume = "50",

pages = "559--571",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Publishing Group",

number = "4",

}

TY - JOUR

T1 - Refining the accuracy of validated target identification through coding variant fine-mapping in type 2 diabetes

AU - Mahajan, Anubha

AU - Wessel, Jennifer

AU - Willems, Sara M.

AU - Zhao, Wei

AU - Robertson, Neil R.

AU - Chu, Audrey Y.

AU - Gan, Wei

AU - Kitajima, Hidetoshi

AU - Taliun, Daniel

AU - Rayner, N. William

AU - Guo, Xiuqing

AU - Lu, Yingchang

AU - Li, Man

AU - Jensen, Richard A.

AU - Hu, Yao

AU - Huo, Shaofeng

AU - Lohman, Kurt K.

AU - Zhang, Weihua

AU - Cook, James P.

AU - Prins, Bram Peter

AU - Flannick, Jason

AU - Grarup, Niels

AU - Trubetskoy, Vassily Vladimirovich

AU - Kravic, Jasmina

AU - Kim, Young Jin

AU - Rybin, Denis V.

AU - Yaghootkar, Hanieh

AU - Müller-Nurasyid, Martina

AU - Meidtner, Karina

AU - Li-Gao, Ruifang

AU - Varga, Tibor V.

AU - Marten, Jonathan

AU - Li, Jin

AU - Smith, Albert Vernon

AU - An, Ping

AU - Ligthart, Symen

AU - Gustafsson, Stefan

AU - Malerba, Giovanni

AU - Demirkan, Ayse

AU - Tajes, Juan Fernandez

AU - Steinthorsdottir, Valgerdur

AU - Wuttke, Matthias

AU - Lecoeur, Cécile

AU - Preuss, Michael

AU - Bielak, Lawrence F.

AU - Graff, Marielisa

AU - Highland, Heather M.

AU - Justice, Anne E.

AU - Liu, Dajiang J.

AU - Marouli, Eirini

AU - Peloso, Gina Marie

AU - Warren, Helen R.

AU - Afaq, Saima

AU - Afzal, Shoaib

AU - Ahlqvist, Emma

AU - Almgren, Peter

AU - Amin, Najaf

AU - Bang, Lia B.

AU - Bertoni, Alain G.

AU - Bombieri, Cristina

AU - Bork-Jensen, Jette

AU - Brandslund, Ivan

AU - Brody, Jennifer A.

AU - Burtt, Noël P.

AU - Canouil, Mickaël

AU - Chen, Yii-Der Ida

AU - Cho, Yoon Shin

AU - Christensen, Cramer

AU - Eastwood, Sophie V.

AU - Eckardt, Kai-Uwe

AU - Fischer, Krista

AU - Gambaro, Giovanni

AU - Giedraitis, Vilmantas

AU - Grove, Megan L.

AU - de Haan, Hugoline G.

AU - Hackinger, Sophie

AU - Hai, Yang

AU - Han, Sohee

AU - Tybjærg-Hansen, Anne

AU - Hivert, Marie-France

AU - Isomaa, Bo

AU - Jäger, Susanne

AU - Jørgensen, Marit E.

AU - Jørgensen, Torben

AU - Käräjämäki, Annemari

AU - Kim, Bong-Jo

AU - Kim, Sung Soo

AU - Koistinen, Heikki A.

AU - Kovacs, Peter

AU - Kriebel, Jennifer

AU - Kronenberg, Florian

AU - Läll, Kristi

AU - Lange, Leslie A.

AU - Lee, Jung-Jin

AU - Lehne, Benjamin

AU - Li, Huaixing

AU - Lin, Keng-Hung

AU - Linneberg, Allan

AU - Liu, Ching-Ti

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N1 - Supplementary information is available for this paper at https://doi.org/10.1038/ s41588-018-0084-1. Acknowledgements A full list of acknowledgments appears in the Supplementary Note. Part of this work was conducted using the UK Biobank Resource under application number 9161.

PY - 2018/4/30

Y1 - 2018/4/30

N2 - We aggregated coding variant data for 81,412 type 2 diabetes cases and 370,832 controls of diverse ancestry, identifying 40 coding variant association signals (P < 2.2 × 10−7); of these, 16 map outside known risk-associated loci. We make two important observations. First, only five of these signals are driven by low-frequency variants: even for these, effect sizes are modest (odds ratio ≤1.29). Second, when we used large-scale genome-wide association data to fine-map the associated variants in their regional context, accounting for the global enrichment of complex trait associations in coding sequence, compelling evidence for coding variant causality was obtained for only 16 signals. At 13 others, the associated coding variants clearly represent ‘false leads’ with potential to generate erroneous mechanistic inference. Coding variant associations offer a direct route to biological insight for complex diseases and identification of validated therapeutic targets; however, appropriate mechanistic inference requires careful specification of their causal contribution to disease predisposition.

AB - We aggregated coding variant data for 81,412 type 2 diabetes cases and 370,832 controls of diverse ancestry, identifying 40 coding variant association signals (P < 2.2 × 10−7); of these, 16 map outside known risk-associated loci. We make two important observations. First, only five of these signals are driven by low-frequency variants: even for these, effect sizes are modest (odds ratio ≤1.29). Second, when we used large-scale genome-wide association data to fine-map the associated variants in their regional context, accounting for the global enrichment of complex trait associations in coding sequence, compelling evidence for coding variant causality was obtained for only 16 signals. At 13 others, the associated coding variants clearly represent ‘false leads’ with potential to generate erroneous mechanistic inference. Coding variant associations offer a direct route to biological insight for complex diseases and identification of validated therapeutic targets; however, appropriate mechanistic inference requires careful specification of their causal contribution to disease predisposition.

UR - https://www.nature.com/authors/policies/license.html

U2 - 10.1038/s41588-018-0084-1

DO - 10.1038/s41588-018-0084-1

M3 - Article

C2 - 29632382

VL - 50

SP - 559

EP - 571

JO - Nature Genetics

JF - Nature Genetics

SN - 1061-4036

IS - 4

ER -

Refining the accuracy of validated target identification through coding variant fine-mapping in type 2 diabetes

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