Meta-analysis of exome array data identifies six novel genetic loci for lung function

Martin D. Tobin; Stephanie J. London; Victoria E. Jackson; Jeanne C. Latourelle; Louise V. Wain; Albert V. Smith; Megan L. Grove; Traci M. Bartz; Ma'en Obeidat; Michael A. Province; Wei Gao; Beenish Qaiser; David J. Porteous; Patricia A. Cassano; Tarunveer S. Ahluwalia; Niels Grarup; Jin Li; Elisabeth Altmaier; Jonathan Marten; Sarah E. Harris; Ani Manichaikul; Tess D. Pottinger; Ruifang Li-Gao; Allan Lind-Thomsen; Anubha Mahajan; Lies Lahousse; Medea Imboden; Alexander Teumer; Bram Prins; Leo Pekka Lyytikäinen; Gudny Eiriksdottir; Nora Franceschini; Colleen M. Sitlani; Jennifer A. Brody; Yohan Bossé; Wim Timens; Aldi Kraja; Anu Loukola; Wenbo Tang; Yongmei Liu; Jette Bork-Jensen; Johanne M. Justesen; Allan Linneberg; Leslie A. Lange; Rajesh Rawal; Stefan Karrasch; Jennifer E. Huffman; Blair H. Smith; Gail Davies; Kristin M. Burkart; Josyf C. Mychaleckyj; Tobias N. Bonten; Stefan Enroth; Lars Lind; Guy G. Brusselle; Ashish Kumar; Beate Stubbe; Mika Kähönen; Annah B. Wyss; Bruce M. Psaty; Susan R. Heckbert; Ke Hao; Taina Rantanen; Stephen B. Kritchevsky; Kurt Lohman; Tea Skaaby; Charlotta Pisinger; Torben Hansen; Holger Schulz; Ozren Polasek; Archie I. Campbell; John M. Starr; Stephen S. Rich; Dennis O. Mook-Kanamori; Åsa Johansson; Erik Ingelsson; André G. Uitterlinden; Stefan Weiss; Olli T. Raitakari; Vilmundur Gudnason; Kari E. North; Sina A. Gharib; Don D. Sin; Kent D. Taylor; George T. O'Connor; Jaakko Kaprio; Tamara B. Harris; Oluf Pederson; Henrik Vestergaard; James G. Wilson; Konstantin Strauch; Caroline Hayward; Shona M. Kerr; Ian J. Deary; R. Graham Barr; Renée de Mutsert; Ulf Gyllensten; Andrew P. Morris; M. Arfan Ikram; Nicole Probst-Hensch; Sven Gläser; Eleftheria Zeggini; Terho Lehtimäki; David P. Strachan; Josée Dupuis; Alanna C. Morrison; Ian P. Hall

doi:10.12688/wellcomeopenres.12583.3

Meta-analysis of exome array data identifies six novel genetic loci for lung function

Martin D. Tobin, Stephanie J. London, Victoria E. Jackson, Jeanne C. Latourelle, Louise V. Wain, Albert V. Smith, Megan L. Grove, Traci M. Bartz, Ma'en Obeidat, Michael A. Province, Wei Gao, Beenish Qaiser, David J. Porteous, Patricia A. Cassano, Tarunveer S. Ahluwalia, Niels Grarup, Jin Li, Elisabeth Altmaier, Jonathan Marten, Sarah E. HarrisAni Manichaikul, Tess D. Pottinger, Ruifang Li-Gao, Allan Lind-Thomsen, Anubha Mahajan, Lies Lahousse, Medea Imboden, Alexander Teumer, Bram Prins, Leo Pekka Lyytikäinen, Gudny Eiriksdottir, Nora Franceschini, Colleen M. Sitlani, Jennifer A. Brody, Yohan Bossé, Wim Timens, Aldi Kraja, Anu Loukola, Wenbo Tang, Yongmei Liu, Jette Bork-Jensen, Johanne M. Justesen, Allan Linneberg, Leslie A. Lange, Rajesh Rawal, Stefan Karrasch, Jennifer E. Huffman, Blair H. Smith, Gail Davies, Kristin M. Burkart, Josyf C. Mychaleckyj, Tobias N. Bonten, Stefan Enroth, Lars Lind, Guy G. Brusselle, Ashish Kumar, Beate Stubbe, Mika Kähönen, Annah B. Wyss, Bruce M. Psaty, Susan R. Heckbert, Ke Hao, Taina Rantanen, Stephen B. Kritchevsky, Kurt Lohman, Tea Skaaby, Charlotta Pisinger, Torben Hansen, Holger Schulz, Ozren Polasek, Archie I. Campbell, John M. Starr, Stephen S. Rich, Dennis O. Mook-Kanamori, Åsa Johansson, Erik Ingelsson, André G. Uitterlinden, Stefan Weiss, Olli T. Raitakari, Vilmundur Gudnason, Kari E. North, Sina A. Gharib, Don D. Sin, Kent D. Taylor, George T. O'Connor, Jaakko Kaprio, Tamara B. Harris, Oluf Pederson, Henrik Vestergaard, James G. Wilson, Konstantin Strauch, Caroline Hayward, Shona M. Kerr, Ian J. Deary, R. Graham Barr, Renée de Mutsert, Ulf Gyllensten, Andrew P. Morris, M. Arfan Ikram, Nicole Probst-Hensch, Sven Gläser, Eleftheria Zeggini, Terho Lehtimäki, David P. Strachan, Josée Dupuis, Alanna C. Morrison, Ian P. Hall

Research output: Contribution to journal › Article › peer-review

3 Scopus citations

Abstract

Background: Over 90 regions of the genome have been associated with lung function to date, many of which have also been implicated in chronic obstructive pulmonary disease. Methods: We carried out meta-analyses of exome array data and three lung function measures: forced expiratory volume in one second (FEV 1), forced vital capacity (FVC) and the ratio of FEV 1 to FVC (FEV 1/FVC). These analyses by the SpiroMeta and CHARGE consortia included 60,749 individuals of European ancestry from 23 studies, and 7,721 individuals of African Ancestry from 5 studies in the discovery stage, with follow-up in up to 111,556 independent individuals. Results: We identified significant (P<28x10 -7) associations with six SNPs: a nonsynonymous variant in RPAP1, which is predicted to be damaging, three intronic SNPs ( SEC24C, CASC17 and UQCC1) and two intergenic SNPs near to LY86 and FGF10. Expression quantitative trait loci analyses found evidence for regulation of gene expression at three signals and implicated several genes, including TYRO3 and PLAU. Conclusions: Further interrogation of these loci could provide greater understanding of the determinants of lung function and pulmonary disease.

Original language	English
Article number	4
Journal	Wellcome Open Research
Volume	3
DOIs	https://doi.org/10.12688/wellcomeopenres.12583.3
State	Published - 2018

Keywords

COPD
Exome array
GWAS
Lung function
Respiratory

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10.12688/wellcomeopenres.12583.3

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Tobin, M. D., London, S. J., Jackson, V. E., Latourelle, J. C., Wain, L. V., Smith, A. V., Grove, M. L., Bartz, T. M., Obeidat, M., Province, M. A., Gao, W., Qaiser, B., Porteous, D. J., Cassano, P. A., Ahluwalia, T. S., Grarup, N., Li, J., Altmaier, E., Marten, J., ... Hall, I. P. (2018). Meta-analysis of exome array data identifies six novel genetic loci for lung function. Wellcome Open Research, 3, Article 4. https://doi.org/10.12688/wellcomeopenres.12583.3

@article{7eb4c00b9fa64172bc3722c36b261680,

title = "Meta-analysis of exome array data identifies six novel genetic loci for lung function",

abstract = "Background: Over 90 regions of the genome have been associated with lung function to date, many of which have also been implicated in chronic obstructive pulmonary disease. Methods: We carried out meta-analyses of exome array data and three lung function measures: forced expiratory volume in one second (FEV 1), forced vital capacity (FVC) and the ratio of FEV 1 to FVC (FEV 1/FVC). These analyses by the SpiroMeta and CHARGE consortia included 60,749 individuals of European ancestry from 23 studies, and 7,721 individuals of African Ancestry from 5 studies in the discovery stage, with follow-up in up to 111,556 independent individuals. Results: We identified significant (P<28x10 -7) associations with six SNPs: a nonsynonymous variant in RPAP1, which is predicted to be damaging, three intronic SNPs ( SEC24C, CASC17 and UQCC1) and two intergenic SNPs near to LY86 and FGF10. Expression quantitative trait loci analyses found evidence for regulation of gene expression at three signals and implicated several genes, including TYRO3 and PLAU. Conclusions: Further interrogation of these loci could provide greater understanding of the determinants of lung function and pulmonary disease.",

keywords = "COPD, Exome array, GWAS, Lung function, Respiratory",

author = "Tobin, {Martin D.} and London, {Stephanie J.} and Jackson, {Victoria E.} and Latourelle, {Jeanne C.} and Wain, {Louise V.} and Smith, {Albert V.} and Grove, {Megan L.} and Bartz, {Traci M.} and Ma'en Obeidat and Province, {Michael A.} and Wei Gao and Beenish Qaiser and Porteous, {David J.} and Cassano, {Patricia A.} and Ahluwalia, {Tarunveer S.} and Niels Grarup and Jin Li and Elisabeth Altmaier and Jonathan Marten and Harris, {Sarah E.} and Ani Manichaikul and Pottinger, {Tess D.} and Ruifang Li-Gao and Allan Lind-Thomsen and Anubha Mahajan and Lies Lahousse and Medea Imboden and Alexander Teumer and Bram Prins and Lyytik{\"a}inen, {Leo Pekka} and Gudny Eiriksdottir and Nora Franceschini and Sitlani, {Colleen M.} and Brody, {Jennifer A.} and Yohan Boss{\'e} and Wim Timens and Aldi Kraja and Anu Loukola and Wenbo Tang and Yongmei Liu and Jette Bork-Jensen and Justesen, {Johanne M.} and Allan Linneberg and Lange, {Leslie A.} and Rajesh Rawal and Stefan Karrasch and Huffman, {Jennifer E.} and Smith, {Blair H.} and Gail Davies and Burkart, {Kristin M.} and Mychaleckyj, {Josyf C.} and Bonten, {Tobias N.} and Stefan Enroth and Lars Lind and Brusselle, {Guy G.} and Ashish Kumar and Beate Stubbe and Mika K{\"a}h{\"o}nen and Wyss, {Annah B.} and Psaty, {Bruce M.} and Heckbert, {Susan R.} and Ke Hao and Taina Rantanen and Kritchevsky, {Stephen B.} and Kurt Lohman and Tea Skaaby and Charlotta Pisinger and Torben Hansen and Holger Schulz and Ozren Polasek and Campbell, {Archie I.} and Starr, {John M.} and Rich, {Stephen S.} and Mook-Kanamori, {Dennis O.} and {\AA}sa Johansson and Erik Ingelsson and Uitterlinden, {Andr{\'e} G.} and Stefan Weiss and Raitakari, {Olli T.} and Vilmundur Gudnason and North, {Kari E.} and Gharib, {Sina A.} and Sin, {Don D.} and Taylor, {Kent D.} and O'Connor, {George T.} and Jaakko Kaprio and Harris, {Tamara B.} and Oluf Pederson and Henrik Vestergaard and Wilson, {James G.} and Konstantin Strauch and Caroline Hayward and Kerr, {Shona M.} and Deary, {Ian J.} and Barr, {R. Graham} and {de Mutsert}, Ren{\'e}e and Ulf Gyllensten and Morris, {Andrew P.} and Ikram, {M. Arfan} and Nicole Probst-Hensch and Sven Gl{\"a}ser and Eleftheria Zeggini and Terho Lehtim{\"a}ki and Strachan, {David P.} and Jos{\'e}e Dupuis and Morrison, {Alanna C.} and Hall, {Ian P.}",

note = "Publisher Copyright: {\textcopyright} 2018 Jackson VE et al.",

year = "2018",

doi = "10.12688/wellcomeopenres.12583.3",

language = "English",

volume = "3",

journal = "Wellcome Open Research",

issn = "2398-502X",

}

Tobin, MD, London, SJ, Jackson, VE, Latourelle, JC, Wain, LV, Smith, AV, Grove, ML, Bartz, TM, Obeidat, M, Province, MA, Gao, W, Qaiser, B, Porteous, DJ, Cassano, PA, Ahluwalia, TS, Grarup, N, Li, J, Altmaier, E, Marten, J, Harris, SE, Manichaikul, A, Pottinger, TD, Li-Gao, R, Lind-Thomsen, A, Mahajan, A, Lahousse, L, Imboden, M, Teumer, A, Prins, B, Lyytikäinen, LP, Eiriksdottir, G, Franceschini, N, Sitlani, CM, Brody, JA, Bossé, Y, Timens, W, Kraja, A, Loukola, A, Tang, W, Liu, Y, Bork-Jensen, J, Justesen, JM, Linneberg, A, Lange, LA, Rawal, R, Karrasch, S, Huffman, JE, Smith, BH, Davies, G, Burkart, KM, Mychaleckyj, JC, Bonten, TN, Enroth, S, Lind, L, Brusselle, GG, Kumar, A, Stubbe, B, Kähönen, M, Wyss, AB, Psaty, BM, Heckbert, SR, Hao, K, Rantanen, T, Kritchevsky, SB, Lohman, K, Skaaby, T, Pisinger, C, Hansen, T, Schulz, H, Polasek, O, Campbell, AI, Starr, JM, Rich, SS, Mook-Kanamori, DO, Johansson, Å, Ingelsson, E, Uitterlinden, AG, Weiss, S, Raitakari, OT, Gudnason, V, North, KE, Gharib, SA, Sin, DD, Taylor, KD, O'Connor, GT, Kaprio, J, Harris, TB, Pederson, O, Vestergaard, H, Wilson, JG, Strauch, K, Hayward, C, Kerr, SM, Deary, IJ, Barr, RG, de Mutsert, R, Gyllensten, U, Morris, AP, Ikram, MA, Probst-Hensch, N, Gläser, S, Zeggini, E, Lehtimäki, T, Strachan, DP, Dupuis, J, Morrison, AC & Hall, IP 2018, 'Meta-analysis of exome array data identifies six novel genetic loci for lung function', Wellcome Open Research, vol. 3, 4. https://doi.org/10.12688/wellcomeopenres.12583.3

TY - JOUR

T1 - Meta-analysis of exome array data identifies six novel genetic loci for lung function

AU - Tobin, Martin D.

AU - London, Stephanie J.

AU - Jackson, Victoria E.

AU - Latourelle, Jeanne C.

AU - Wain, Louise V.

AU - Smith, Albert V.

AU - Grove, Megan L.

AU - Bartz, Traci M.

AU - Obeidat, Ma'en

AU - Province, Michael A.

AU - Gao, Wei

AU - Qaiser, Beenish

AU - Porteous, David J.

AU - Cassano, Patricia A.

AU - Ahluwalia, Tarunveer S.

AU - Grarup, Niels

AU - Li, Jin

AU - Altmaier, Elisabeth

AU - Marten, Jonathan

AU - Harris, Sarah E.

AU - Manichaikul, Ani

AU - Pottinger, Tess D.

AU - Li-Gao, Ruifang

AU - Lind-Thomsen, Allan

AU - Mahajan, Anubha

AU - Lahousse, Lies

AU - Imboden, Medea

AU - Teumer, Alexander

AU - Prins, Bram

AU - Lyytikäinen, Leo Pekka

AU - Eiriksdottir, Gudny

AU - Franceschini, Nora

AU - Sitlani, Colleen M.

AU - Brody, Jennifer A.

AU - Bossé, Yohan

AU - Timens, Wim

AU - Kraja, Aldi

AU - Loukola, Anu

AU - Tang, Wenbo

AU - Liu, Yongmei

AU - Bork-Jensen, Jette

AU - Justesen, Johanne M.

AU - Linneberg, Allan

AU - Lange, Leslie A.

AU - Rawal, Rajesh

AU - Karrasch, Stefan

AU - Huffman, Jennifer E.

AU - Smith, Blair H.

AU - Davies, Gail

AU - Burkart, Kristin M.

AU - Mychaleckyj, Josyf C.

AU - Bonten, Tobias N.

AU - Enroth, Stefan

AU - Lind, Lars

AU - Brusselle, Guy G.

AU - Kumar, Ashish

AU - Stubbe, Beate

AU - Kähönen, Mika

AU - Wyss, Annah B.

AU - Psaty, Bruce M.

AU - Heckbert, Susan R.

AU - Hao, Ke

AU - Rantanen, Taina

AU - Kritchevsky, Stephen B.

AU - Lohman, Kurt

AU - Skaaby, Tea

AU - Pisinger, Charlotta

AU - Hansen, Torben

AU - Schulz, Holger

AU - Polasek, Ozren

AU - Campbell, Archie I.

AU - Starr, John M.

AU - Rich, Stephen S.

AU - Mook-Kanamori, Dennis O.

AU - Johansson, Åsa

AU - Ingelsson, Erik

AU - Uitterlinden, André G.

AU - Weiss, Stefan

AU - Raitakari, Olli T.

AU - Gudnason, Vilmundur

AU - North, Kari E.

AU - Gharib, Sina A.

AU - Sin, Don D.

AU - Taylor, Kent D.

AU - O'Connor, George T.

AU - Kaprio, Jaakko

AU - Harris, Tamara B.

AU - Pederson, Oluf

AU - Vestergaard, Henrik

AU - Wilson, James G.

AU - Strauch, Konstantin

AU - Hayward, Caroline

AU - Kerr, Shona M.

AU - Deary, Ian J.

AU - Barr, R. Graham

AU - de Mutsert, Renée

AU - Gyllensten, Ulf

AU - Morris, Andrew P.

AU - Ikram, M. Arfan

AU - Probst-Hensch, Nicole

AU - Gläser, Sven

AU - Zeggini, Eleftheria

AU - Lehtimäki, Terho

AU - Strachan, David P.

AU - Dupuis, Josée

AU - Morrison, Alanna C.

AU - Hall, Ian P.

PY - 2018

Y1 - 2018

N2 - Background: Over 90 regions of the genome have been associated with lung function to date, many of which have also been implicated in chronic obstructive pulmonary disease. Methods: We carried out meta-analyses of exome array data and three lung function measures: forced expiratory volume in one second (FEV 1), forced vital capacity (FVC) and the ratio of FEV 1 to FVC (FEV 1/FVC). These analyses by the SpiroMeta and CHARGE consortia included 60,749 individuals of European ancestry from 23 studies, and 7,721 individuals of African Ancestry from 5 studies in the discovery stage, with follow-up in up to 111,556 independent individuals. Results: We identified significant (P<28x10 -7) associations with six SNPs: a nonsynonymous variant in RPAP1, which is predicted to be damaging, three intronic SNPs ( SEC24C, CASC17 and UQCC1) and two intergenic SNPs near to LY86 and FGF10. Expression quantitative trait loci analyses found evidence for regulation of gene expression at three signals and implicated several genes, including TYRO3 and PLAU. Conclusions: Further interrogation of these loci could provide greater understanding of the determinants of lung function and pulmonary disease.

AB - Background: Over 90 regions of the genome have been associated with lung function to date, many of which have also been implicated in chronic obstructive pulmonary disease. Methods: We carried out meta-analyses of exome array data and three lung function measures: forced expiratory volume in one second (FEV 1), forced vital capacity (FVC) and the ratio of FEV 1 to FVC (FEV 1/FVC). These analyses by the SpiroMeta and CHARGE consortia included 60,749 individuals of European ancestry from 23 studies, and 7,721 individuals of African Ancestry from 5 studies in the discovery stage, with follow-up in up to 111,556 independent individuals. Results: We identified significant (P<28x10 -7) associations with six SNPs: a nonsynonymous variant in RPAP1, which is predicted to be damaging, three intronic SNPs ( SEC24C, CASC17 and UQCC1) and two intergenic SNPs near to LY86 and FGF10. Expression quantitative trait loci analyses found evidence for regulation of gene expression at three signals and implicated several genes, including TYRO3 and PLAU. Conclusions: Further interrogation of these loci could provide greater understanding of the determinants of lung function and pulmonary disease.

KW - COPD

KW - Exome array

KW - GWAS

KW - Lung function

KW - Respiratory

UR - http://www.scopus.com/inward/record.url?scp=85062156888&partnerID=8YFLogxK

U2 - 10.12688/wellcomeopenres.12583.3

DO - 10.12688/wellcomeopenres.12583.3

M3 - Article

AN - SCOPUS:85062156888

SN - 2398-502X

VL - 3

JO - Wellcome Open Research

JF - Wellcome Open Research

M1 - 4

ER -

Meta-analysis of exome array data identifies six novel genetic loci for lung function

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