Discovery and refinement of genetic loci associated with cardiometabolic risk using dense imputation maps

Valentina Lotchkova; Jie Huang; John Morris; Deepti Jain; Caterina Barbieri; Klaudia Walter; Josine Min; Lu Chen; William J Astle; Massimiliano Cocca; Patrick Deelen; Heather Elding; Aliki-Eleni Farmaki; Christopher S Franklin; Mattias Franberg; Tom Gaunt; Albert Hofman; Tao Jiang; Marcus E Kleber; Geneviève Lachance; Jian'an Luan; Giovanni Malerba; Angela Matchan; Daniel Mead; Yasin Memari; Ioanna Ntalla; Kalliope Panoutsopoulou; Raha Pazoki; John R B Perry; Fernando Rivadeneira; Maria Sabater-Lleal; Bengt Sennblad; So-Youn Shin; Lorraine Southam; Michela Traglia; Freerk van Dijk; Elisabeth M van Leeuwen; Gianluigi Zaza; Weihua Zhang; Najaf Amin; Adam Butterworth; John C Chambers; George V Dedoussis; Abbas Dehghan; Oscar H Franco; Lude Franke; Mattia Frontini; Giovanni Gambaro; Paolo Gasparini; Anders Hamsten; Aaron Issacs; Jaspal S Kooner; Charles L Kooperberg; Claudia Langenberg; Winfried Marz; Robert A Scott; Morris A Swertz; Daniela Toniolo; André G Uitterlinden; Cornelia M van Duijn; Hugh Watkins; Eleftheria Zeggini; Matthew T Maurano; Nicholas Timpson; Alexander P Reiner; Paul L Auer; Nicole Soranzo

doi:10.1038/ng.3668

Discovery and refinement of genetic loci associated with cardiometabolic risk using dense imputation maps

Valentina Lotchkova, Jie Huang, John Morris, Deepti Jain, Caterina Barbieri, Klaudia Walter, Josine Min, Lu Chen, William J Astle, Massimiliano Cocca, Patrick Deelen, Heather Elding, Aliki-Eleni Farmaki, Christopher S Franklin, Mattias Franberg, Tom Gaunt, Albert Hofman, Tao Jiang, Marcus E Kleber, Geneviève LachanceJian'an Luan, Giovanni Malerba, Angela Matchan, Daniel Mead, Yasin Memari, Ioanna Ntalla, Kalliope Panoutsopoulou, Raha Pazoki, John R B Perry, Fernando Rivadeneira, Maria Sabater-Lleal, Bengt Sennblad, So-Youn Shin, Lorraine Southam, Michela Traglia, Freerk van Dijk, Elisabeth M van Leeuwen, Gianluigi Zaza, Weihua Zhang, Najaf Amin, Adam Butterworth, John C Chambers, George V Dedoussis, Abbas Dehghan, Oscar H Franco, Lude Franke, Mattia Frontini, Giovanni Gambaro, Paolo Gasparini, Anders Hamsten, Aaron Issacs, Jaspal S Kooner, Charles L Kooperberg, Claudia Langenberg, Winfried Marz, Robert A Scott, Morris A Swertz, Daniela Toniolo, André G Uitterlinden, Cornelia M van Duijn, Hugh Watkins, Eleftheria Zeggini, Matthew T Maurano, Nicholas Timpson, Alexander P Reiner, Paul L Auer, Nicole Soranzo

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Abstract

Large-scale whole-genome sequence data sets offer novel opportunities to identify genetic variation underlying human traits. Here we apply genotype imputation based on whole-genome sequence data from the UK10K and 1000 Genomes Project into 35,981 study participants of European ancestry, followed by association analysis with 20 quantitative cardiometabolic and hematological traits. We describe 17 new associations, including 6 rare (minor allele frequency (MAF) < 1%) or low-frequency (1% < MAF < 5%) variants with platelet count (PLT), red blood cell indices (MCH and MCV) and HDL cholesterol. Applying fine-mapping analysis to 233 known and new loci associated with the 20 traits, we resolve the associations of 59 loci to credible sets of 20 or fewer variants and describe trait enrichments within regions of predicted regulatory function. These findings improve understanding of the allelic architecture of risk factors for cardiometabolic and hematological diseases and provide additional functional insights with the identification of potentially novel biological targets.

Original language	English
Pages (from-to)	1303–1312
Number of pages	12
Journal	Nature Genetics
Volume	48
Issue number	11
Early online date	26 Sept 2016
DOIs	https://doi.org/10.1038/ng.3668
Publication status	Published - Nov 2016

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Timpson, N. J. (Principal Investigator) & Timpson, N. J. (Principal Investigator)
1/06/13 → 31/03/18
Project: Research

Professor Nicholas John Timpson
- N.J.Timpsonbristol.acuk
- Bristol Medical School (PHS) - Professor of Genetic Epidemiology
- Bristol Population Health Science Institute
- MRC Integrative Epidemiology Unit
- Cancer
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Lotchkova, V., Huang, J., Morris, J., Jain, D., Barbieri, C., Walter, K., Min, J., Chen, L., Astle, W. J., Cocca, M., Deelen, P., Elding, H., Farmaki, A.-E., Franklin, C. S., Franberg, M., Gaunt, T., Hofman, A., Jiang, T., Kleber, M. E., ... Soranzo, N. (2016). Discovery and refinement of genetic loci associated with cardiometabolic risk using dense imputation maps. Nature Genetics, 48(11), 1303–1312. https://doi.org/10.1038/ng.3668

@article{b10cbd247f554fdc90b2d051b6b9d253,

title = "Discovery and refinement of genetic loci associated with cardiometabolic risk using dense imputation maps",

abstract = "Large-scale whole-genome sequence data sets offer novel opportunities to identify genetic variation underlying human traits. Here we apply genotype imputation based on whole-genome sequence data from the UK10K and 1000 Genomes Project into 35,981 study participants of European ancestry, followed by association analysis with 20 quantitative cardiometabolic and hematological traits. We describe 17 new associations, including 6 rare (minor allele frequency (MAF) < 1%) or low-frequency (1% < MAF < 5%) variants with platelet count (PLT), red blood cell indices (MCH and MCV) and HDL cholesterol. Applying fine-mapping analysis to 233 known and new loci associated with the 20 traits, we resolve the associations of 59 loci to credible sets of 20 or fewer variants and describe trait enrichments within regions of predicted regulatory function. These findings improve understanding of the allelic architecture of risk factors for cardiometabolic and hematological diseases and provide additional functional insights with the identification of potentially novel biological targets.",

author = "Valentina Lotchkova and Jie Huang and John Morris and Deepti Jain and Caterina Barbieri and Klaudia Walter and Josine Min and Lu Chen and Astle, {William J} and Massimiliano Cocca and Patrick Deelen and Heather Elding and Aliki-Eleni Farmaki and Franklin, {Christopher S} and Mattias Franberg and Tom Gaunt and Albert Hofman and Tao Jiang and Kleber, {Marcus E} and Genevi{\`e}ve Lachance and Jian'an Luan and Giovanni Malerba and Angela Matchan and Daniel Mead and Yasin Memari and Ioanna Ntalla and Kalliope Panoutsopoulou and Raha Pazoki and Perry, {John R B} and Fernando Rivadeneira and Maria Sabater-Lleal and Bengt Sennblad and So-Youn Shin and Lorraine Southam and Michela Traglia and {van Dijk}, Freerk and {van Leeuwen}, {Elisabeth M} and Gianluigi Zaza and Weihua Zhang and Najaf Amin and Adam Butterworth and Chambers, {John C} and Dedoussis, {George V} and Abbas Dehghan and Franco, {Oscar H} and Lude Franke and Mattia Frontini and Giovanni Gambaro and Paolo Gasparini and Anders Hamsten and Aaron Issacs and Kooner, {Jaspal S} and {L Kooperberg}, Charles and Claudia Langenberg and Winfried Marz and Scott, {Robert A} and Swertz, {Morris A} and Daniela Toniolo and Uitterlinden, {Andr{\'e} G} and {van Duijn}, {Cornelia M} and Hugh Watkins and Eleftheria Zeggini and Maurano, {Matthew T} and Nicholas Timpson and Reiner, {Alexander P} and Auer, {Paul L} and Nicole Soranzo",

year = "2016",

month = nov,

doi = "10.1038/ng.3668",

language = "English",

volume = "48",

pages = "1303–1312",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Springer Nature",

number = "11",

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Lotchkova, V, Huang, J, Morris, J, Jain, D, Barbieri, C, Walter, K, Min, J, Chen, L, Astle, WJ, Cocca, M, Deelen, P, Elding, H, Farmaki, A-E, Franklin, CS, Franberg, M, Gaunt, T, Hofman, A, Jiang, T, Kleber, ME, Lachance, G, Luan, J, Malerba, G, Matchan, A, Mead, D, Memari, Y, Ntalla, I, Panoutsopoulou, K, Pazoki, R, Perry, JRB, Rivadeneira, F, Sabater-Lleal, M, Sennblad, B, Shin, S-Y, Southam, L, Traglia, M, van Dijk, F, van Leeuwen, EM, Zaza, G, Zhang, W, Amin, N, Butterworth, A, Chambers, JC, Dedoussis, GV, Dehghan, A, Franco, OH, Franke, L, Frontini, M, Gambaro, G, Gasparini, P, Hamsten, A, Issacs, A, Kooner, JS, L Kooperberg, C, Langenberg, C, Marz, W, Scott, RA, Swertz, MA, Toniolo, D, Uitterlinden, AG, van Duijn, CM, Watkins, H, Zeggini, E, Maurano, MT, Timpson, N, Reiner, AP, Auer, PL & Soranzo, N 2016, 'Discovery and refinement of genetic loci associated with cardiometabolic risk using dense imputation maps', Nature Genetics, vol. 48, no. 11, pp. 1303–1312. https://doi.org/10.1038/ng.3668

TY - JOUR

T1 - Discovery and refinement of genetic loci associated with cardiometabolic risk using dense imputation maps

AU - Lotchkova, Valentina

AU - Huang, Jie

AU - Morris, John

AU - Jain, Deepti

AU - Barbieri, Caterina

AU - Walter, Klaudia

AU - Min, Josine

AU - Chen, Lu

AU - Astle, William J

AU - Cocca, Massimiliano

AU - Deelen, Patrick

AU - Elding, Heather

AU - Farmaki, Aliki-Eleni

AU - Franklin, Christopher S

AU - Franberg, Mattias

AU - Gaunt, Tom

AU - Hofman, Albert

AU - Jiang, Tao

AU - Kleber, Marcus E

AU - Lachance, Geneviève

AU - Luan, Jian'an

AU - Malerba, Giovanni

AU - Matchan, Angela

AU - Mead, Daniel

AU - Memari, Yasin

AU - Ntalla, Ioanna

AU - Panoutsopoulou, Kalliope

AU - Pazoki, Raha

AU - Perry, John R B

AU - Rivadeneira, Fernando

AU - Sabater-Lleal, Maria

AU - Sennblad, Bengt

AU - Shin, So-Youn

AU - Southam, Lorraine

AU - Traglia, Michela

AU - van Dijk, Freerk

AU - van Leeuwen, Elisabeth M

AU - Zaza, Gianluigi

AU - Zhang, Weihua

AU - Amin, Najaf

AU - Butterworth, Adam

AU - Chambers, John C

AU - Dedoussis, George V

AU - Dehghan, Abbas

AU - Franco, Oscar H

AU - Franke, Lude

AU - Frontini, Mattia

AU - Gambaro, Giovanni

AU - Gasparini, Paolo

AU - Hamsten, Anders

AU - Issacs, Aaron

AU - Kooner, Jaspal S

AU - L Kooperberg, Charles

AU - Langenberg, Claudia

AU - Marz, Winfried

AU - Scott, Robert A

AU - Swertz, Morris A

AU - Toniolo, Daniela

AU - Uitterlinden, André G

AU - van Duijn, Cornelia M

AU - Watkins, Hugh

AU - Zeggini, Eleftheria

AU - Maurano, Matthew T

AU - Timpson, Nicholas

AU - Reiner, Alexander P

AU - Auer, Paul L

AU - Soranzo, Nicole

PY - 2016/11

Y1 - 2016/11

N2 - Large-scale whole-genome sequence data sets offer novel opportunities to identify genetic variation underlying human traits. Here we apply genotype imputation based on whole-genome sequence data from the UK10K and 1000 Genomes Project into 35,981 study participants of European ancestry, followed by association analysis with 20 quantitative cardiometabolic and hematological traits. We describe 17 new associations, including 6 rare (minor allele frequency (MAF) < 1%) or low-frequency (1% < MAF < 5%) variants with platelet count (PLT), red blood cell indices (MCH and MCV) and HDL cholesterol. Applying fine-mapping analysis to 233 known and new loci associated with the 20 traits, we resolve the associations of 59 loci to credible sets of 20 or fewer variants and describe trait enrichments within regions of predicted regulatory function. These findings improve understanding of the allelic architecture of risk factors for cardiometabolic and hematological diseases and provide additional functional insights with the identification of potentially novel biological targets.

AB - Large-scale whole-genome sequence data sets offer novel opportunities to identify genetic variation underlying human traits. Here we apply genotype imputation based on whole-genome sequence data from the UK10K and 1000 Genomes Project into 35,981 study participants of European ancestry, followed by association analysis with 20 quantitative cardiometabolic and hematological traits. We describe 17 new associations, including 6 rare (minor allele frequency (MAF) < 1%) or low-frequency (1% < MAF < 5%) variants with platelet count (PLT), red blood cell indices (MCH and MCV) and HDL cholesterol. Applying fine-mapping analysis to 233 known and new loci associated with the 20 traits, we resolve the associations of 59 loci to credible sets of 20 or fewer variants and describe trait enrichments within regions of predicted regulatory function. These findings improve understanding of the allelic architecture of risk factors for cardiometabolic and hematological diseases and provide additional functional insights with the identification of potentially novel biological targets.

U2 - 10.1038/ng.3668

DO - 10.1038/ng.3668

M3 - Article (Academic Journal)

C2 - 27668658

SN - 1061-4036

VL - 48

SP - 1303

EP - 1312

JO - Nature Genetics

JF - Nature Genetics

IS - 11

ER -

Discovery and refinement of genetic loci associated with cardiometabolic risk using dense imputation maps

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