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

    22 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

    Fingerprint

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

    Cite this

    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.
    @article{a8ce6fb6298e464fb39874382527cf5e,
    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 = "anthropometry, DXA traits, genetic association study, imputation, next-generation whole-genome sequencing, UK Biobank, UK10K",
    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 Farmaki, {Aliki Eleni} 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 Lin, {Wei Yu} and Adam Locke and Jian'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 = "6",
    day = "1",
    doi = "10.1016/j.ajhg.2017.04.014",
    language = "English",
    volume = "100",
    pages = "865--884",
    journal = "The American Journal of Human Genetics",
    issn = "0002-9297",
    publisher = "UNIV CHICAGO PRESS",
    number = "6",

    }

    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 -