Whole-Genome Sequencing Coupled to Imputation Discovers Genetic Signals for Anthropometric Traits

Ioanna Tachmazidou; Dániel Süveges; Josine L. Min; Graham R.S. Ritchie; Julia Steinberg; Klaudia Walter; Valentina Iotchkova; Jeremy Schwartzentruber; Jie Huang; Yasin Memari; Shane McCarthy; Andrew A. Crawford; Cristina Bombieri; Massimiliano Cocca; Aliki-Eleni Farmaki; Tom R. Gaunt; Pekka Jousilahti; Marjolein N. Kooijman; Benjamin Lehne; Giovanni Malerba; Satu Männistö; Angela Matchan; Carolina Medina-Gomez; Sarah J. Metrustry; Abhishek Nag; Ioanna Ntalla; Lavinia Paternoster; Nigel W. Rayner; Cinzia Sala; William R. Scott; Hashem A. Shihab; Lorraine Southam; Beate St Pourcain; Michela Traglia; Katerina Trajanoska; Gialuigi Zaza; Weihua Zhang; María S. Artigas; Narinder Bansal; Marianne Benn; Zhongsheng Chen; Petr Danecek; Wei-Yu Lin; Adam Locke; Jian’an Luan; Alisa K. Manning; Antonella Mulas; Carlo Sidore; Anne Tybjaerg-Hansen; Anette Varbo; Magdalena Zoledziewska; Chris Finan; Konstantinos Hatzikotoulas; Audrey E. Hendricks; John P. Kemp; Alireza Moayyeri; Kalliope Panoutsopoulou; Michal Szpak; Scott G. Wilson; Michael Boehnke; Francesco Cucca; Emanuele Di Angelantonio; Claudia Langenberg; Cecilia Lindgren; Mark I. McCarthy; Andrew P. Morris; Børge G. Nordestgaard; Robert A. Scott; Martin D. Tobin; Nicholas J. Wareham; Paul Burton; John C. Chambers; George Davey Smith; George Dedoussis; Janine F. Felix; Oscar H. Franco; Giovanni Gambaro; Paolo Gasparini; Christopher J. Hammond; Albert Hofman; Vincent W.V. Jaddoe; Marcus Kleber; Jaspal S. Kooner; Markus Perola; Caroline Relton; Susan M. Ring; Fernando Rivadeneira; Veikko Salomaa; Timothy D. Spector; Oliver Stegle; Daniela Toniolo; André G. Uitterlinden; Inês Barroso; Celia M.T. Greenwood; John R.B. Perry; Brian R. Walker; Adam S. Butterworth; Yali Xue; Richard Durbin; Kerrin S. Small; Nicole Soranzo; Nicholas J. Timpson; Eleftheria Zeggini

doi:10.1016/j.ajhg.2017.04.014

Whole-Genome Sequencing Coupled to Imputation Discovers Genetic Signals for Anthropometric Traits

Ioanna Tachmazidou, Dániel Süveges, Josine L. Min, Graham R.S. Ritchie, Julia Steinberg, Klaudia Walter, Valentina Iotchkova, Jeremy Schwartzentruber, Jie Huang, Yasin Memari, Shane McCarthy, Andrew A. Crawford, Cristina Bombieri, Massimiliano Cocca, Aliki-Eleni Farmaki, Tom R. Gaunt, Pekka Jousilahti, Marjolein N. Kooijman, Benjamin Lehne, Giovanni MalerbaSatu Männistö, Angela Matchan, Carolina Medina-Gomez, Sarah J. Metrustry, Abhishek Nag, Ioanna Ntalla, Lavinia Paternoster, Nigel W. Rayner, Cinzia Sala, William R. Scott, Hashem A. Shihab, Lorraine Southam, Beate St Pourcain, Michela Traglia, Katerina Trajanoska, Gialuigi Zaza, Weihua Zhang, María S. Artigas, Narinder Bansal, Marianne Benn, Zhongsheng Chen, Petr Danecek, Wei-Yu Lin, Adam Locke, Jian’an Luan, Alisa K. Manning, Antonella Mulas, Carlo Sidore, Anne Tybjaerg-Hansen, Anette Varbo, Magdalena Zoledziewska, Chris Finan, Konstantinos Hatzikotoulas, Audrey E. Hendricks, John P. Kemp, Alireza Moayyeri, Kalliope Panoutsopoulou, Michal Szpak, Scott G. Wilson, Michael Boehnke, Francesco Cucca, Emanuele Di Angelantonio, Claudia Langenberg, Cecilia Lindgren, Mark I. McCarthy, Andrew P. Morris, Børge G. Nordestgaard, Robert A. Scott, Martin D. Tobin, Nicholas J. Wareham, Paul Burton, John C. Chambers, George Davey Smith, George Dedoussis, Janine F. Felix, Oscar H. Franco, Giovanni Gambaro, Paolo Gasparini, Christopher J. Hammond, Albert Hofman, Vincent W.V. Jaddoe, Marcus Kleber, Jaspal S. Kooner, Markus Perola, Caroline Relton, Susan M. Ring, Fernando Rivadeneira, Veikko Salomaa, Timothy D. Spector, Oliver Stegle, Daniela Toniolo, André G. Uitterlinden, Inês Barroso, Celia M.T. Greenwood, John R.B. Perry, Brian R. Walker, Adam S. Butterworth, Yali Xue, Richard Durbin, Kerrin S. Small, Nicole Soranzo, Nicholas J. Timpson, Eleftheria Zeggini

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Abstract

Deep sequence-based imputation can enhance the discovery power of genome-wide association studies by assessing previously unexplored variation across the common- and low-frequency spectra. We applied a hybrid whole-genome sequencing (WGS) and deep imputation approach to examine the broader allelic architecture of 12 anthropometric traits associated with height, body mass, and fat distribution in up to 267,616 individuals. We report 106 genome-wide significant signals that have not been previously identified, including 9 low-frequency variants pointing to functional candidates. Of the 106 signals, 6 are in genomic regions that have not been implicated with related traits before, 28 are independent signals at previously reported regions, and 72 represent previously reported signals for a different anthropometric trait. 71% of signals reside within genes and fine mapping resolves 23 signals to one or two likely causal variants. We confirm genetic overlap between human monogenic and polygenic anthropometric traits and find signal enrichment in cis expression QTLs in relevant tissues. Our results highlight the potential of WGS strategies to enhance biologically relevant discoveries across the frequency spectrum.

Original language	English
Pages (from-to)	865–884
Journal	American Journal of Human Genetics
Volume	100
Issue number	6
Early online date	25 May 2017
DOIs	https://doi.org/10.1016/j.ajhg.2017.04.014
Publication status	Published - 1 Jun 2017

Keywords

UK10K
genetic association study
next-generation whole-genome sequencing
imputation
UK Biobank
anthropometry
DXA traits

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Whole-Genome Sequencing Coupled to_TACHMAZIDOU_Firstonline25May2017_GOLD VoR (CC-BY)Final published version, 2.75 MBLicence: CC BY

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Tachmazidou, I., Süveges, D., Min, J. L., Ritchie, G. R. S., Steinberg, J., Walter, K., Iotchkova, V., Schwartzentruber, J., Huang, J., Memari, Y., McCarthy, S., Crawford, A. A., Bombieri, C., Cocca, M., Farmaki, A.-E., Gaunt, T. R., Jousilahti, P., Kooijman, M. N., Lehne, B., ... Zeggini, E. (2017). Whole-Genome Sequencing Coupled to Imputation Discovers Genetic Signals for Anthropometric Traits. American Journal of Human Genetics, 100(6), 865–884. https://doi.org/10.1016/j.ajhg.2017.04.014

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title = "Whole-Genome Sequencing Coupled to Imputation Discovers Genetic Signals for Anthropometric Traits",

abstract = "Deep sequence-based imputation can enhance the discovery power of genome-wide association studies by assessing previously unexplored variation across the common- and low-frequency spectra. We applied a hybrid whole-genome sequencing (WGS) and deep imputation approach to examine the broader allelic architecture of 12 anthropometric traits associated with height, body mass, and fat distribution in up to 267,616 individuals. We report 106 genome-wide significant signals that have not been previously identified, including 9 low-frequency variants pointing to functional candidates. Of the 106 signals, 6 are in genomic regions that have not been implicated with related traits before, 28 are independent signals at previously reported regions, and 72 represent previously reported signals for a different anthropometric trait. 71% of signals reside within genes and fine mapping resolves 23 signals to one or two likely causal variants. We confirm genetic overlap between human monogenic and polygenic anthropometric traits and find signal enrichment in cis expression QTLs in relevant tissues. Our results highlight the potential of WGS strategies to enhance biologically relevant discoveries across the frequency spectrum.",

keywords = "UK10K, genetic association study, next-generation whole-genome sequencing, imputation, UK Biobank, anthropometry, DXA traits",

author = "Ioanna Tachmazidou and D{\'a}niel S{\"u}veges and Min, {Josine L.} and Ritchie, {Graham R.S.} and Julia Steinberg and Klaudia Walter and Valentina Iotchkova and Jeremy Schwartzentruber and Jie Huang and Yasin Memari and Shane McCarthy and Crawford, {Andrew A.} and Cristina Bombieri and Massimiliano Cocca and Aliki-Eleni Farmaki and Gaunt, {Tom R.} and Pekka Jousilahti and Kooijman, {Marjolein N.} and Benjamin Lehne and Giovanni Malerba and Satu M{\"a}nnist{\"o} and Angela Matchan and Carolina Medina-Gomez and Metrustry, {Sarah J.} and Abhishek Nag and Ioanna Ntalla and Lavinia Paternoster and Rayner, {Nigel W.} and Cinzia Sala and Scott, {William R.} and Shihab, {Hashem A.} and Lorraine Southam and {St Pourcain}, Beate and Michela Traglia and Katerina Trajanoska and Gialuigi Zaza and Weihua Zhang and Artigas, {Mar{\'i}a S.} and Narinder Bansal and Marianne Benn and Zhongsheng Chen and Petr Danecek and Wei-Yu Lin and Adam Locke and Jian{\textquoteright}an Luan and Manning, {Alisa K.} and Antonella Mulas and Carlo Sidore and Anne Tybjaerg-Hansen and Anette Varbo and Magdalena Zoledziewska and Chris Finan and Konstantinos Hatzikotoulas and Hendricks, {Audrey E.} and Kemp, {John P.} and Alireza Moayyeri and Kalliope Panoutsopoulou and Michal Szpak and Wilson, {Scott G.} and Michael Boehnke and Francesco Cucca and {Di Angelantonio}, Emanuele and Claudia Langenberg and Cecilia Lindgren and McCarthy, {Mark I.} and Morris, {Andrew P.} and Nordestgaard, {B{\o}rge G.} and Scott, {Robert A.} and Tobin, {Martin D.} and Wareham, {Nicholas J.} and Paul Burton and Chambers, {John C.} and Smith, {George Davey} and George Dedoussis and Felix, {Janine F.} and Franco, {Oscar H.} and Giovanni Gambaro and Paolo Gasparini and Hammond, {Christopher J.} and Albert Hofman and Jaddoe, {Vincent W.V.} and Marcus Kleber and Kooner, {Jaspal S.} and Markus Perola and Caroline Relton and Ring, {Susan M.} and Fernando Rivadeneira and Veikko Salomaa and Spector, {Timothy D.} and Oliver Stegle and Daniela Toniolo and Uitterlinden, {Andr{\'e} G.} and In{\^e}s Barroso and Greenwood, {Celia M.T.} and Perry, {John R.B.} and Walker, {Brian R.} and Butterworth, {Adam S.} and Yali Xue and Richard Durbin and Small, {Kerrin S.} and Nicole Soranzo and Timpson, {Nicholas J.} and Eleftheria Zeggini",

year = "2017",

month = jun,

day = "1",

doi = "10.1016/j.ajhg.2017.04.014",

language = "English",

volume = "100",

pages = "865–884",

journal = "American Journal of Human Genetics",

issn = "0002-9297",

publisher = "Elsevier",

number = "6",

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Tachmazidou, I, Süveges, D, Min, JL, Ritchie, GRS, Steinberg, J, Walter, K, Iotchkova, V, Schwartzentruber, J, Huang, J, Memari, Y, McCarthy, S, Crawford, AA, Bombieri, C, Cocca, M, Farmaki, A-E, Gaunt, TR, Jousilahti, P, Kooijman, MN, Lehne, B, Malerba, G, Männistö, S, Matchan, A, Medina-Gomez, C, Metrustry, SJ , Nag, A, Ntalla, I, Paternoster, L, Rayner, NW, Sala, C, Scott, WR, Shihab, HA, Southam, L, St Pourcain, B, Traglia, M, Trajanoska, K, Zaza, G, Zhang, W, Artigas, MS, Bansal, N, Benn, M, Chen, Z, Danecek, P, Lin, W-Y, Locke, A, Luan, J, Manning, AK, Mulas, A, Sidore, C, Tybjaerg-Hansen, A, Varbo, A, Zoledziewska, M, Finan, C, Hatzikotoulas, K, Hendricks, AE, Kemp, JP, Moayyeri, A, Panoutsopoulou, K, Szpak, M, Wilson, SG, Boehnke, M, Cucca, F, Di Angelantonio, E, Langenberg, C, Lindgren, C, McCarthy, MI, Morris, AP, Nordestgaard, BG, Scott, RA, Tobin, MD, Wareham, NJ, Burton, P, Chambers, JC, Smith, GD, Dedoussis, G, Felix, JF, Franco, OH, Gambaro, G, Gasparini, P, Hammond, CJ, Hofman, A, Jaddoe, VWV, Kleber, M, Kooner, JS, Perola, M, Relton, C, Ring, SM, Rivadeneira, F, Salomaa, V, Spector, TD, Stegle, O, Toniolo, D, Uitterlinden, AG, Barroso, I, Greenwood, CMT, Perry, JRB, Walker, BR, Butterworth, AS, Xue, Y, Durbin, R, Small, KS, Soranzo, N, Timpson, NJ & Zeggini, E 2017, 'Whole-Genome Sequencing Coupled to Imputation Discovers Genetic Signals for Anthropometric Traits', American Journal of Human Genetics, vol. 100, no. 6, pp. 865–884. https://doi.org/10.1016/j.ajhg.2017.04.014

TY - JOUR

T1 - Whole-Genome Sequencing Coupled to Imputation Discovers Genetic Signals for Anthropometric Traits

AU - Tachmazidou, Ioanna

AU - Süveges, Dániel

AU - Min, Josine L.

AU - Ritchie, Graham R.S.

AU - Steinberg, Julia

AU - Walter, Klaudia

AU - Iotchkova, Valentina

AU - Schwartzentruber, Jeremy

AU - Huang, Jie

AU - Memari, Yasin

AU - McCarthy, Shane

AU - Crawford, Andrew A.

AU - Bombieri, Cristina

AU - Cocca, Massimiliano

AU - Farmaki, Aliki-Eleni

AU - Gaunt, Tom R.

AU - Jousilahti, Pekka

AU - Kooijman, Marjolein N.

AU - Lehne, Benjamin

AU - Malerba, Giovanni

AU - Männistö, Satu

AU - Matchan, Angela

AU - Medina-Gomez, Carolina

AU - Metrustry, Sarah J.

AU - Nag, Abhishek

AU - Ntalla, Ioanna

AU - Paternoster, Lavinia

AU - Rayner, Nigel W.

AU - Sala, Cinzia

AU - Scott, William R.

AU - Shihab, Hashem A.

AU - Southam, Lorraine

AU - St Pourcain, Beate

AU - Traglia, Michela

AU - Trajanoska, Katerina

AU - Zaza, Gialuigi

AU - Zhang, Weihua

AU - Artigas, María S.

AU - Bansal, Narinder

AU - Benn, Marianne

AU - Chen, Zhongsheng

AU - Danecek, Petr

AU - Lin, Wei-Yu

AU - Locke, Adam

AU - Luan, Jian’an

AU - Manning, Alisa K.

AU - Mulas, Antonella

AU - Sidore, Carlo

AU - Tybjaerg-Hansen, Anne

AU - Varbo, Anette

AU - Zoledziewska, Magdalena

AU - Finan, Chris

AU - Hatzikotoulas, Konstantinos

AU - Hendricks, Audrey E.

AU - Kemp, John P.

AU - Moayyeri, Alireza

AU - Panoutsopoulou, Kalliope

AU - Szpak, Michal

AU - Wilson, Scott G.

AU - Boehnke, Michael

AU - Cucca, Francesco

AU - Di Angelantonio, Emanuele

AU - Langenberg, Claudia

AU - Lindgren, Cecilia

AU - McCarthy, Mark I.

AU - Morris, Andrew P.

AU - Nordestgaard, Børge G.

AU - Scott, Robert A.

AU - Tobin, Martin D.

AU - Wareham, Nicholas J.

AU - Burton, Paul

AU - Chambers, John C.

AU - Smith, George Davey

AU - Dedoussis, George

AU - Felix, Janine F.

AU - Franco, Oscar H.

AU - Gambaro, Giovanni

AU - Gasparini, Paolo

AU - Hammond, Christopher J.

AU - Hofman, Albert

AU - Jaddoe, Vincent W.V.

AU - Kleber, Marcus

AU - Kooner, Jaspal S.

AU - Perola, Markus

AU - Relton, Caroline

AU - Ring, Susan M.

AU - Rivadeneira, Fernando

AU - Salomaa, Veikko

AU - Spector, Timothy D.

AU - Stegle, Oliver

AU - Toniolo, Daniela

AU - Uitterlinden, André G.

AU - Barroso, Inês

AU - Greenwood, Celia M.T.

AU - Perry, John R.B.

AU - Walker, Brian R.

AU - Butterworth, Adam S.

AU - Xue, Yali

AU - Durbin, Richard

AU - Small, Kerrin S.

AU - Soranzo, Nicole

AU - Timpson, Nicholas J.

AU - Zeggini, Eleftheria

PY - 2017/6/1

Y1 - 2017/6/1

N2 - Deep sequence-based imputation can enhance the discovery power of genome-wide association studies by assessing previously unexplored variation across the common- and low-frequency spectra. We applied a hybrid whole-genome sequencing (WGS) and deep imputation approach to examine the broader allelic architecture of 12 anthropometric traits associated with height, body mass, and fat distribution in up to 267,616 individuals. We report 106 genome-wide significant signals that have not been previously identified, including 9 low-frequency variants pointing to functional candidates. Of the 106 signals, 6 are in genomic regions that have not been implicated with related traits before, 28 are independent signals at previously reported regions, and 72 represent previously reported signals for a different anthropometric trait. 71% of signals reside within genes and fine mapping resolves 23 signals to one or two likely causal variants. We confirm genetic overlap between human monogenic and polygenic anthropometric traits and find signal enrichment in cis expression QTLs in relevant tissues. Our results highlight the potential of WGS strategies to enhance biologically relevant discoveries across the frequency spectrum.

AB - Deep sequence-based imputation can enhance the discovery power of genome-wide association studies by assessing previously unexplored variation across the common- and low-frequency spectra. We applied a hybrid whole-genome sequencing (WGS) and deep imputation approach to examine the broader allelic architecture of 12 anthropometric traits associated with height, body mass, and fat distribution in up to 267,616 individuals. We report 106 genome-wide significant signals that have not been previously identified, including 9 low-frequency variants pointing to functional candidates. Of the 106 signals, 6 are in genomic regions that have not been implicated with related traits before, 28 are independent signals at previously reported regions, and 72 represent previously reported signals for a different anthropometric trait. 71% of signals reside within genes and fine mapping resolves 23 signals to one or two likely causal variants. We confirm genetic overlap between human monogenic and polygenic anthropometric traits and find signal enrichment in cis expression QTLs in relevant tissues. Our results highlight the potential of WGS strategies to enhance biologically relevant discoveries across the frequency spectrum.

KW - UK10K

KW - genetic association study

KW - next-generation whole-genome sequencing

KW - imputation

KW - UK Biobank

KW - anthropometry

KW - DXA traits

U2 - 10.1016/j.ajhg.2017.04.014

DO - 10.1016/j.ajhg.2017.04.014

M3 - Article

SN - 0002-9297

VL - 100

SP - 865

EP - 884

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

IS - 6

ER -

Whole-Genome Sequencing Coupled to Imputation Discovers Genetic Signals for Anthropometric Traits

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