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 & 83 others 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

Research output: Contribution to journalArticle

23 Citations (Scopus)

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 languageEnglish
Pages (from-to)865-884
Number of pages20
JournalAmerican Journal of Human Genetics
Volume100
Issue number6
DOIs
Publication statusPublished - 1 Jun 2017

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Genome
Multifactorial Inheritance
Body Fat Distribution
High-Throughput Nucleotide Sequencing
Chromosome Mapping
Genome-Wide Association Study

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Tachmazidou, I., Süveges, D., Min, J. L., Ritchie, G. R. S., Steinberg, J., Walter, K., ... 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
Tachmazidou, Ioanna ; Süveges, Dániel ; Min, Josine L. ; Ritchie, Graham R.S. ; Steinberg, Julia ; Walter, Klaudia ; Iotchkova, Valentina ; Schwartzentruber, Jeremy ; Huang, Jie ; Memari, Yasin ; McCarthy, Shane ; Crawford, Andrew A. ; Bombieri, Cristina ; Cocca, Massimiliano ; Farmaki, Aliki Eleni ; Gaunt, Tom R. ; Jousilahti, Pekka ; Kooijman, Marjolein N. ; Lehne, Benjamin ; Malerba, Giovanni ; Männistö, Satu ; Matchan, Angela ; Medina-Gomez, Carolina ; Metrustry, Sarah J. ; Nag, Abhishek ; Ntalla, Ioanna ; Paternoster, Lavinia ; Rayner, Nigel W. ; Sala, Cinzia ; Scott, William R. ; Shihab, Hashem A. ; Southam, Lorraine ; St Pourcain, Beate ; Traglia, Michela ; Trajanoska, Katerina ; Zaza, Gialuigi ; Zhang, Weihua ; Artigas, María S. ; Bansal, Narinder ; Benn, Marianne ; Chen, Zhongsheng ; Danecek, Petr ; Lin, Wei Yu ; Locke, Adam ; Luan, Jian'an ; Manning, Alisa K. ; Mulas, Antonella ; Sidore, Carlo ; Tybjaerg-Hansen, Anne ; Varbo, Anette ; Zoledziewska, Magdalena ; Finan, Chris ; Hatzikotoulas, Konstantinos ; Hendricks, Audrey E. ; Kemp, John P. ; Moayyeri, Alireza ; Panoutsopoulou, Kalliope ; Szpak, Michal ; Wilson, Scott G. ; Boehnke, Michael ; Cucca, Francesco ; Di Angelantonio, Emanuele ; Langenberg, Claudia ; Lindgren, Cecilia ; McCarthy, Mark I. ; Morris, Andrew P. ; Nordestgaard, Børge G. ; Scott, Robert A. ; Tobin, Martin D. ; Wareham, Nicholas J. ; Burton, Paul ; Chambers, John C. ; Smith, George Davey ; Dedoussis, George ; Felix, Janine F. ; Franco, Oscar H. ; Gambaro, Giovanni ; Gasparini, Paolo ; Hammond, Christopher J. ; Hofman, Albert ; Jaddoe, Vincent W.V. ; Kleber, Marcus ; Kooner, Jaspal S. ; Perola, Markus ; Relton, Caroline ; Ring, Susan M. ; Rivadeneira, Fernando ; Salomaa, Veikko ; Spector, Timothy D. ; Stegle, Oliver ; Toniolo, Daniela ; Uitterlinden, André G. ; Barroso, Inês ; Greenwood, Celia M.T. ; Perry, John R.B. ; Walker, Brian R. ; Butterworth, Adam S. ; Xue, Yali ; Durbin, Richard ; Small, Kerrin S. ; Soranzo, Nicole ; Timpson, Nicholas J. ; Zeggini, Eleftheria. / Whole-Genome Sequencing Coupled to Imputation Discovers Genetic Signals for Anthropometric Traits. In: American Journal of Human Genetics. 2017 ; Vol. 100, No. 6. pp. 865-884.
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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, AE, 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, WY, 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

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

In: American Journal of Human Genetics, Vol. 100, No. 6, 01.06.2017, p. 865-884.

Research output: Contribution to journalArticle

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 - anthropometry

KW - DXA traits

KW - genetic association study

KW - imputation

KW - next-generation whole-genome sequencing

KW - UK Biobank

KW - UK10K

UR - http://www.scopus.com/inward/record.url?scp=85019940063&partnerID=8YFLogxK

U2 - 10.1016/j.ajhg.2017.04.014

DO - 10.1016/j.ajhg.2017.04.014

M3 - Article

VL - 100

SP - 865

EP - 884

JO - The American Journal of Human Genetics

JF - The American Journal of Human Genetics

SN - 0002-9297

IS - 6

ER -