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

Research output: Contribution to journal › Journal article › Research › peer-review

1016 Citations (Scopus)

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
Journal	Nature Genetics
Volume	50
Issue number	11
Pages (from-to)	1505-1513
Number of pages	9
ISSN	1061-4036
DOIs	https://doi.org/10.1038/s41588-018-0241-6
Publication status	Published - Nov 2018

Keywords

Body Mass Index
Case-Control Studies
Chromosome Mapping/methods
Diabetes Mellitus, Type 2/epidemiology
Epigenesis, Genetic
European Continental Ancestry Group/genetics
Female
Gene Frequency
Genetic Loci/genetics
Genetic Predisposition to Disease
Genome, Human/genetics
Genome-Wide Association Study
High-Throughput Screening Assays/methods
Humans
Islets of Langerhans/metabolism
Linkage Disequilibrium
Male
Meta-Analysis as Topic
Polymorphism, Single Nucleotide
Sex Factors

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10.1038/s41588-018-0241-6

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6287706/pdf/emss-80721.pdf

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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).",

keywords = "Body Mass Index, Case-Control Studies, Chromosome Mapping/methods, Diabetes Mellitus, Type 2/epidemiology, Epigenesis, Genetic, European Continental Ancestry Group/genetics, Female, Gene Frequency, Genetic Loci/genetics, Genetic Predisposition to Disease, Genome, Human/genetics, Genome-Wide Association Study, High-Throughput Screening Assays/methods, Humans, Islets of Langerhans/metabolism, Linkage Disequilibrium, Male, Meta-Analysis as Topic, Polymorphism, Single Nucleotide, Sex Factors",

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 Ching-Ti Liu and Locke, {Adam E} and Jian'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}",

year = "2018",

month = nov,

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

language = "English",

volume = "50",

pages = "1505--1513",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Publishing Group",

number = "11",

}

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, K-U, Fischer, K, Kardia, SLR, Kronenberg, F, Läll, K, Liu, C-T, 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

Y1 - 2018/11

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).

KW - Body Mass Index

KW - Case-Control Studies

KW - Chromosome Mapping/methods

KW - Diabetes Mellitus, Type 2/epidemiology

KW - Epigenesis, Genetic

KW - European Continental Ancestry Group/genetics

KW - Female

KW - Gene Frequency

KW - Genetic Loci/genetics

KW - Genetic Predisposition to Disease

KW - Genome, Human/genetics

KW - Genome-Wide Association Study

KW - High-Throughput Screening Assays/methods

KW - Humans

KW - Islets of Langerhans/metabolism

KW - Linkage Disequilibrium

KW - Male

KW - Meta-Analysis as Topic

KW - Polymorphism, Single Nucleotide

KW - Sex Factors

U2 - 10.1038/s41588-018-0241-6

DO - 10.1038/s41588-018-0241-6

M3 - Journal article

C2 - 30297969

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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