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

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

doi:10.1038/s41588-018-0241-6

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

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. PreussBram 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

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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).

Original language	English
Pages (from-to)	1505-1513
Number of pages	9
Journal	Nature Genetics
Volume	50
Issue number	11
DOIs	https://doi.org/10.1038/s41588-018-0241-6
State	Published - 1 Nov 2018

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10.1038/s41588-018-0241-6

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Mahajan, A., Taliun, D., Thurner, M., Robertson, N. R., Torres, J. M., Rayner, N. W., Payne, A. J., Steinthorsdottir, V., Scott, R. A., Grarup, N., Cook, J. P., Schmidt, E. M., Wuttke, M., Sarnowski, C., Mägi, R., Nano, J., Gieger, C., Trompet, S., Lecoeur, C., ... McCarthy, M. I. (2018). Fine-mapping type 2 diabetes loci to single-variant resolution using high-density imputation and islet-specific epigenome maps. Nature Genetics, 50(11), 1505-1513. https://doi.org/10.1038/s41588-018-0241-6

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

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).",

author = "Anubha Mahajan and Daniel Taliun and Matthias Thurner and Robertson, {Neil R.} and Torres, {Jason M.} and Rayner, {N. William} and Payne, {Anthony J.} and Valgerdur Steinthorsdottir and Scott, {Robert A.} and Niels Grarup and Cook, {James P.} and Schmidt, {Ellen M.} and Matthias Wuttke and Chlo{\'e} Sarnowski and Reedik M{\"a}gi and Jana Nano and Christian Gieger and Stella Trompet and C{\'e}cile Lecoeur and Preuss, {Michael H.} and Prins, {Bram Peter} and Xiuqing Guo and Bielak, {Lawrence F.} and Below, {Jennifer E.} and Bowden, {Donald W.} and Chambers, {John Campbell} and Kim, {Young Jin} and Ng, {Maggie C.Y.} and Petty, {Lauren E.} and Xueling Sim and Weihua Zhang and Bennett, {Amanda J.} and Jette Bork-Jensen and Brummett, {Chad M.} and Micka{\"e}l Canouil and {Ec kardt}, {Kai Uwe} and Krista Fischer and Kardia, {Sharon L.R.} and Florian Kronenberg and Kristi L{\"a}ll and Liu, {Ching Ti} and Locke, {Adam E.} and Jian{\textquoteright}an Luan and Ioanna Ntalla and Vibe Nylander and Sebastian Sch{\"o}nherr and Claudia Schurmann and Lo{\"i}c Yengo and Bottinger, {Erwin P.} and Ivan Brandslund and Cramer Christensen and George Dedoussis and Florez, {Jose C.} and Ian Ford and Franco, {Oscar H.} and Frayling, {Timothy M.} and Vilmantas Giedraitis and Sophie Hackinger and Hattersley, {Andrew T.} and Christian Herder and Ikram, {M. Arfan} and Martin Ingelsson and J{\o}rgensen, {Marit E.} and Torben J{\o}rgensen and Jennifer Kriebel and Johanna Kuusisto and Symen Ligthart and Lindgren, {Cecilia M.} and Allan Linneberg and Valeriya Lyssenko and Vasiliki Mamakou and Thomas Meitinger and Mohlke, {Karen L.} and Morris, {Andrew D.} and Girish Nadkarni and Pankow, {James S.} and Annette Peters and Naveed Sattar and Alena Stan{\v c}{\'a}kov{\'a} and Konstantin Strauch and Taylor, {Kent D.} and Barbara Thorand and Gudmar Thorleifsson and Unnur Thorsteinsdottir and Jaakko Tuomilehto and Witte, {Daniel R.} and Jos{\'e}e Dupuis and Peyser, {Patricia A.} and Eleftheria Zeggini and Loos, {Ruth J.F.} and Philippe Froguel and Erik Ingelsson and Lars Lind and Leif Groop and Markku Laakso and Collins, {Francis S.} and Jukema, {J. Wouter} and Palmer, {Colin N.A.} and Harald Grallert and Andres Metspalu and Abbas Dehghan and Anna K{\"o}ttgen and Abecasis, {Goncalo R.} and Meigs, {James B.} and Rotter, {Jerome I.} and Jonathan Marchini and Oluf Pedersen and Torben Hansen and Claudia Langenberg and Wareham, {Nicholas J.} and Kari Stefansson and Gloyn, {Anna L.} and Morris, {Andrew P.} and Michael Boehnke and McCarthy, {Mark I.}",

note = "Publisher Copyright: {\textcopyright} 2018, The Author(s), under exclusive licence to Springer Nature America, Inc.",

year = "2018",

month = nov,

day = "1",

doi = "10.1038/s41588-018-0241-6",

language = "English",

volume = "50",

pages = "1505--1513",

journal = "Nature Genetics",

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Mahajan, A, Taliun, D, Thurner, M, Robertson, NR, Torres, JM, Rayner, NW, Payne, AJ, Steinthorsdottir, V, Scott, RA, Grarup, N, Cook, JP, Schmidt, EM, Wuttke, M, Sarnowski, C, Mägi, R, Nano, J, Gieger, C, Trompet, S, Lecoeur, C, Preuss, MH, Prins, BP, Guo, X, Bielak, LF, Below, JE, Bowden, DW, Chambers, JC, Kim, YJ, Ng, MCY, Petty, LE, Sim, X, Zhang, W, Bennett, AJ, Bork-Jensen, J, Brummett, CM, Canouil, M, Ec kardt, KU, Fischer, K, Kardia, SLR, Kronenberg, F, Läll, K, Liu, CT, Locke, AE, Luan, J, Ntalla, I, Nylander, V, Schönherr, S, Schurmann, C, Yengo, L, Bottinger, EP, Brandslund, I, Christensen, C, Dedoussis, G, Florez, JC, Ford, I, Franco, OH, Frayling, TM, Giedraitis, V, Hackinger, S, Hattersley, AT, Herder, C, Ikram, MA, Ingelsson, M, Jørgensen, ME, Jørgensen, T, Kriebel, J, Kuusisto, J, Ligthart, S, Lindgren, CM, Linneberg, A, Lyssenko, V, Mamakou, V, Meitinger, T, Mohlke, KL, Morris, AD, Nadkarni, G, Pankow, JS, Peters, A, Sattar, N, Stančáková, A, Strauch, K, Taylor, KD, Thorand, B, Thorleifsson, G, Thorsteinsdottir, U, Tuomilehto, J, Witte, DR, Dupuis, J, Peyser, PA, Zeggini, E, Loos, RJF, Froguel, P, Ingelsson, E, Lind, L, Groop, L, Laakso, M, Collins, FS, Jukema, JW, Palmer, CNA, Grallert, H, Metspalu, A, Dehghan, A, Köttgen, A, Abecasis, GR, Meigs, JB, Rotter, JI, Marchini, J, Pedersen, O, Hansen, T, Langenberg, C, Wareham, NJ, Stefansson, K, Gloyn, AL, Morris, AP, Boehnke, M & McCarthy, MI 2018, 'Fine-mapping type 2 diabetes loci to single-variant resolution using high-density imputation and islet-specific epigenome maps', Nature Genetics, vol. 50, no. 11, pp. 1505-1513. https://doi.org/10.1038/s41588-018-0241-6

TY - JOUR

T1 - Fine-mapping type 2 diabetes loci to single-variant resolution using high-density imputation and islet-specific epigenome maps

AU - Mahajan, Anubha

AU - Taliun, Daniel

AU - Thurner, Matthias

AU - Robertson, Neil R.

AU - Torres, Jason M.

AU - Rayner, N. William

AU - Payne, Anthony J.

AU - Steinthorsdottir, Valgerdur

AU - Scott, Robert A.

AU - Grarup, Niels

AU - Cook, James P.

AU - Schmidt, Ellen M.

AU - Wuttke, Matthias

AU - Sarnowski, Chloé

AU - Mägi, Reedik

AU - Nano, Jana

AU - Gieger, Christian

AU - Trompet, Stella

AU - Lecoeur, Cécile

AU - Preuss, Michael H.

AU - Prins, Bram Peter

AU - Guo, Xiuqing

AU - Bielak, Lawrence F.

AU - Below, Jennifer E.

AU - Bowden, Donald W.

AU - Chambers, John Campbell

AU - Kim, Young Jin

AU - Ng, Maggie C.Y.

AU - Petty, Lauren E.

AU - Sim, Xueling

AU - Zhang, Weihua

AU - Bennett, Amanda J.

AU - Bork-Jensen, Jette

AU - Brummett, Chad M.

AU - Canouil, Mickaël

AU - Ec kardt, Kai Uwe

AU - Fischer, Krista

AU - Kardia, Sharon L.R.

AU - Kronenberg, Florian

AU - Läll, Kristi

AU - Liu, Ching Ti

AU - Locke, Adam E.

AU - Luan, Jian’an

AU - Ntalla, Ioanna

AU - Nylander, Vibe

AU - Schönherr, Sebastian

AU - Schurmann, Claudia

AU - Yengo, Loïc

AU - Bottinger, Erwin P.

AU - Brandslund, Ivan

AU - Christensen, Cramer

AU - Dedoussis, George

AU - Florez, Jose C.

AU - Ford, Ian

AU - Franco, Oscar H.

AU - Frayling, Timothy M.

AU - Giedraitis, Vilmantas

AU - Hackinger, Sophie

AU - Hattersley, Andrew T.

AU - Herder, Christian

AU - Ikram, M. Arfan

AU - Ingelsson, Martin

AU - Jørgensen, Marit E.

AU - Jørgensen, Torben

AU - Kriebel, Jennifer

AU - Kuusisto, Johanna

AU - Ligthart, Symen

AU - Lindgren, Cecilia M.

AU - Linneberg, Allan

AU - Lyssenko, Valeriya

AU - Mamakou, Vasiliki

AU - Meitinger, Thomas

AU - Mohlke, Karen L.

AU - Morris, Andrew D.

AU - Nadkarni, Girish

AU - Pankow, James S.

AU - Peters, Annette

AU - Sattar, Naveed

AU - Stančáková, Alena

AU - Strauch, Konstantin

AU - Taylor, Kent D.

AU - Thorand, Barbara

AU - Thorleifsson, Gudmar

AU - Thorsteinsdottir, Unnur

AU - Tuomilehto, Jaakko

AU - Witte, Daniel R.

AU - Dupuis, Josée

AU - Peyser, Patricia A.

AU - Zeggini, Eleftheria

AU - Loos, Ruth J.F.

AU - Froguel, Philippe

AU - Ingelsson, Erik

AU - Lind, Lars

AU - Groop, Leif

AU - Laakso, Markku

AU - Collins, Francis S.

AU - Jukema, J. Wouter

AU - Palmer, Colin N.A.

AU - Grallert, Harald

AU - Metspalu, Andres

AU - Dehghan, Abbas

AU - Köttgen, Anna

AU - Abecasis, Goncalo R.

AU - Meigs, James B.

AU - Rotter, Jerome I.

AU - Marchini, Jonathan

AU - Pedersen, Oluf

AU - Hansen, Torben

AU - Langenberg, Claudia

AU - Wareham, Nicholas J.

AU - Stefansson, Kari

AU - Gloyn, Anna L.

AU - Morris, Andrew P.

AU - Boehnke, Michael

AU - McCarthy, Mark I.

PY - 2018/11/1

Y1 - 2018/11/1

N2 - 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).

AB - 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).

UR - http://www.scopus.com/inward/record.url?scp=85050198390&partnerID=8YFLogxK

U2 - 10.1038/s41588-018-0241-6

DO - 10.1038/s41588-018-0241-6

M3 - Article

C2 - 30297969

AN - SCOPUS:85050198390

SN - 1061-4036

VL - 50

SP - 1505

EP - 1513

JO - Nature Genetics

JF - Nature Genetics

IS - 11

ER -

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

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