Exome-wide analysis of rare coding variation identifies novel associations with COPD and airflow limitation in MOCS3, IFIT3 and SERPINA12

Victoria E. Jackson; Ioanna Ntalla; Ian Sayers; Richard Morris; Peter Whincup; Juan-Pablo Casas; Antoinette Amuzu; Minkyoung Choi; Caroline Dale; Meena Kumari; Jorgen Engmann; Noor Kalsheker; Sally Chappell; Tamar Guetta-Baranes; Tricia M. McKeever; Colin N. A. Palmer; Roger Tavendale; John W. Holloway; Avan A. Sayer; Elaine M. Dennison; Cyrus Cooper; Mona Bafadhel; Bethan Barker; Chris Brightling; Charlotte E. Bolton; Michelle E. John; Stuart G. Parker; Miriam F. Moffat; Andrew J. Wardlaw; Martin J. Connolly; David J. Porteous; Blair H. Smith; Sandosh Padmanabhan; Lynne Hocking; Kathleen E. Stirrups; Panos Deloukas; David P. Strachan; Ian P. Hall; Martin D. Tobin; Louise V. Wain

doi:10.1136/thoraxjnl-2015-207876

Exome-wide analysis of rare coding variation identifies novel associations with COPD and airflow limitation in MOCS3, IFIT3 and SERPINA12

Victoria E. Jackson, Ioanna Ntalla, Ian Sayers, Richard Morris, Peter Whincup, Juan-Pablo Casas, Antoinette Amuzu, Minkyoung Choi, Caroline Dale, Meena Kumari, Jorgen Engmann, Noor Kalsheker, Sally Chappell, Tamar Guetta-Baranes, Tricia M. McKeever, Colin N. A. Palmer, Roger Tavendale, John W. Holloway, Avan A. Sayer, Elaine M. DennisonCyrus Cooper, Mona Bafadhel, Bethan Barker, Chris Brightling, Charlotte E. Bolton, Michelle E. John, Stuart G. Parker, Miriam F. Moffat, Andrew J. Wardlaw, Martin J. Connolly, David J. Porteous, Blair H. Smith, Sandosh Padmanabhan, Lynne Hocking, Kathleen E. Stirrups, Panos Deloukas, David P. Strachan, Ian P. Hall, Martin D. Tobin, Louise V. Wain

Applied Medicine

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Abstract

BACKGROUND: Several regions of the genome have shown to be associated with COPD in genome-wide association studies of common variants.

OBJECTIVE: To determine rare and potentially functional single nucleotide polymorphisms (SNPs) associated with the risk of COPD and severity of airflow limitation.

METHODS: 3226 current or former smokers of European ancestry with lung function measures indicative of Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2 COPD or worse were genotyped using an exome array. An analysis of risk of COPD was carried out using ever smoking controls (n=4784). Associations with %predicted FEV1 were tested in cases. We followed-up signals of interest (p<10(-5)) in independent samples from a subset of the UK Biobank population and also undertook a more powerful discovery study by meta-analysing the exome array data and UK Biobank data for variants represented on both arrays.

RESULTS: Among the associated variants were two in regions previously unreported for COPD; a low frequency non-synonymous SNP in MOCS3 (rs7269297, pdiscovery=3.08×10(-6), preplication=0.019) and a rare SNP in IFIT3, which emerged in the meta-analysis (rs140549288, pmeta=8.56×10(-6)). In the meta-analysis of % predicted FEV1 in cases, the strongest association was shown for a splice variant in a previously unreported region, SERPINA12 (rs140198372, pmeta=5.72×10(-6)). We also confirmed previously reported associations with COPD risk at MMP12, HHIP, GPR126 and CHRNA5. No associations in novel regions reached a stringent exome-wide significance threshold (p<3.7×10(-7)).

CONCLUSIONS: This study identified several associations with the risk of COPD and severity of airflow limitation, including novel regions MOCS3, IFIT3 and SERPINA12, which warrant further study.

Original language	English
Pages (from-to)	501-509
Number of pages	9
Journal	Thorax
Volume	71
Issue number	6
Early online date	25 Feb 2016
DOIs	https://doi.org/10.1136/thoraxjnl-2015-207876
Publication status	Published - Jun 2016

Bibliographical note

Funding
British Women’s Heart and Health Study is funded by the Department of Health grant no. 90049 and the British Heart Foundation grant no. PG/09/022. British Regional Heart Study is supported by the British Heart Foundation (grant RG/13/16/30528). CB (COPDBEAT) received funding from the Medical Research Council UK (grant no. G0601369), CB (COPDBEAT) and AJW (UKCOPD) were supported by the National Institute for Health Research (NIHR Leicester Biomedical Research Unit). MB (COPDBEAT) received funding from the NIHR (grant no. PDF-2013-06-052). Hertfordshire Cohort Study received support from the Medical Research Council, Arthritis Research UK, the International Osteoporosis Foundation and the British Heart Foundation; NIHR Biomedical Research Centre in Nutrition, University of Southampton; NIHR Musculoskeletal Biomedical Research Unit, University of Oxford. Generation Scotland: Scottish Family Health Study is funded by the Chief Scientist Office, Scottish Government Health Directorates, grant number CZD/16/6 and the Scottish Funding Council grant HR03006. EU COPD Gene Scan is funded by the European Union, grant no. QLG1-CT-2001-01012. English Longitudinal Study of Aging is funded by the Institute of Aging, NIH grant No. AG1764406S1. GoDARTs is funded by the Wellcome Trust grants 072960, 084726 and 104970. MDT has been supported by MRC fellowship G0902313. UK Biobank Lung Exome Variant Evaluation study was funded by a Medical Research Council strategic award to MDT, IPH, DPS and LVW (MC_PC_12010).

Acknowledgements
This research used the ALICE and SPECTRE High Performance Computing Facilities at the University of Leicester and was supported by the National Institute for Health Research (NIHR) Leicester Respiratory Biomedical Research Unit. This article/paper/report presents independent research funded partially by the NIHR. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. This research has been conducted using the UK Biobank Resource.

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Exome-wide analysis of rare coding variation identifies novel associations with COPD and airflow limitation in MOCS3, IFIT3 and SERPINA12
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Jackson, V. E., Ntalla, I., Sayers, I., Morris, R., Whincup, P., Casas, J.-P., Amuzu, A., Choi, M., Dale, C., Kumari, M., Engmann, J., Kalsheker, N., Chappell, S., Guetta-Baranes, T., McKeever, T. M., Palmer, C. N. A., Tavendale, R., Holloway, J. W., Sayer, A. A., ... Wain, L. V. (2016). Exome-wide analysis of rare coding variation identifies novel associations with COPD and airflow limitation in MOCS3, IFIT3 and SERPINA12. Thorax, 71(6), 501-509. https://doi.org/10.1136/thoraxjnl-2015-207876

Jackson, VE, Ntalla, I, Sayers, I, Morris, R, Whincup, P, Casas, J-P, Amuzu, A, Choi, M, Dale, C, Kumari, M, Engmann, J, Kalsheker, N, Chappell, S, Guetta-Baranes, T, McKeever, TM, Palmer, CNA, Tavendale, R, Holloway, JW, Sayer, AA, Dennison, EM, Cooper, C, Bafadhel, M, Barker, B, Brightling, C, Bolton, CE, John, ME, Parker, SG, Moffat, MF, Wardlaw, AJ, Connolly, MJ, Porteous, DJ, Smith, BH, Padmanabhan, S, Hocking, L, Stirrups, KE, Deloukas, P, Strachan, DP, Hall, IP, Tobin, MD & Wain, LV 2016, 'Exome-wide analysis of rare coding variation identifies novel associations with COPD and airflow limitation in MOCS3, IFIT3 and SERPINA12', Thorax, vol. 71, no. 6, pp. 501-509. https://doi.org/10.1136/thoraxjnl-2015-207876

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title = "Exome-wide analysis of rare coding variation identifies novel associations with COPD and airflow limitation in MOCS3, IFIT3 and SERPINA12",

abstract = "BACKGROUND: Several regions of the genome have shown to be associated with COPD in genome-wide association studies of common variants.OBJECTIVE: To determine rare and potentially functional single nucleotide polymorphisms (SNPs) associated with the risk of COPD and severity of airflow limitation.METHODS: 3226 current or former smokers of European ancestry with lung function measures indicative of Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2 COPD or worse were genotyped using an exome array. An analysis of risk of COPD was carried out using ever smoking controls (n=4784). Associations with %predicted FEV1 were tested in cases. We followed-up signals of interest (p<10(-5)) in independent samples from a subset of the UK Biobank population and also undertook a more powerful discovery study by meta-analysing the exome array data and UK Biobank data for variants represented on both arrays.RESULTS: Among the associated variants were two in regions previously unreported for COPD; a low frequency non-synonymous SNP in MOCS3 (rs7269297, pdiscovery=3.08×10(-6), preplication=0.019) and a rare SNP in IFIT3, which emerged in the meta-analysis (rs140549288, pmeta=8.56×10(-6)). In the meta-analysis of % predicted FEV1 in cases, the strongest association was shown for a splice variant in a previously unreported region, SERPINA12 (rs140198372, pmeta=5.72×10(-6)). We also confirmed previously reported associations with COPD risk at MMP12, HHIP, GPR126 and CHRNA5. No associations in novel regions reached a stringent exome-wide significance threshold (p<3.7×10(-7)).CONCLUSIONS: This study identified several associations with the risk of COPD and severity of airflow limitation, including novel regions MOCS3, IFIT3 and SERPINA12, which warrant further study.",

author = "Jackson, {Victoria E.} and Ioanna Ntalla and Ian Sayers and Richard Morris and Peter Whincup and Juan-Pablo Casas and Antoinette Amuzu and Minkyoung Choi and Caroline Dale and Meena Kumari and Jorgen Engmann and Noor Kalsheker and Sally Chappell and Tamar Guetta-Baranes and McKeever, {Tricia M.} and Palmer, {Colin N. A.} and Roger Tavendale and Holloway, {John W.} and Sayer, {Avan A.} and Dennison, {Elaine M.} and Cyrus Cooper and Mona Bafadhel and Bethan Barker and Chris Brightling and Bolton, {Charlotte E.} and John, {Michelle E.} and Parker, {Stuart G.} and Moffat, {Miriam F.} and Wardlaw, {Andrew J.} and Connolly, {Martin J.} and Porteous, {David J.} and Smith, {Blair H.} and Sandosh Padmanabhan and Lynne Hocking and Stirrups, {Kathleen E.} and Panos Deloukas and Strachan, {David P.} and Hall, {Ian P.} and Tobin, {Martin D.} and Wain, {Louise V.}",

note = "Funding British Women{\textquoteright}s Heart and Health Study is funded by the Department of Health grant no. 90049 and the British Heart Foundation grant no. PG/09/022. British Regional Heart Study is supported by the British Heart Foundation (grant RG/13/16/30528). CB (COPDBEAT) received funding from the Medical Research Council UK (grant no. G0601369), CB (COPDBEAT) and AJW (UKCOPD) were supported by the National Institute for Health Research (NIHR Leicester Biomedical Research Unit). MB (COPDBEAT) received funding from the NIHR (grant no. PDF-2013-06-052). Hertfordshire Cohort Study received support from the Medical Research Council, Arthritis Research UK, the International Osteoporosis Foundation and the British Heart Foundation; NIHR Biomedical Research Centre in Nutrition, University of Southampton; NIHR Musculoskeletal Biomedical Research Unit, University of Oxford. Generation Scotland: Scottish Family Health Study is funded by the Chief Scientist Office, Scottish Government Health Directorates, grant number CZD/16/6 and the Scottish Funding Council grant HR03006. EU COPD Gene Scan is funded by the European Union, grant no. QLG1-CT-2001-01012. English Longitudinal Study of Aging is funded by the Institute of Aging, NIH grant No. AG1764406S1. GoDARTs is funded by the Wellcome Trust grants 072960, 084726 and 104970. MDT has been supported by MRC fellowship G0902313. UK Biobank Lung Exome Variant Evaluation study was funded by a Medical Research Council strategic award to MDT, IPH, DPS and LVW (MC_PC_12010). Acknowledgements This research used the ALICE and SPECTRE High Performance Computing Facilities at the University of Leicester and was supported by the National Institute for Health Research (NIHR) Leicester Respiratory Biomedical Research Unit. This article/paper/report presents independent research funded partially by the NIHR. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. This research has been conducted using the UK Biobank Resource.",

year = "2016",

month = jun,

doi = "10.1136/thoraxjnl-2015-207876",

language = "English",

volume = "71",

pages = "501--509",

journal = "Thorax",

issn = "0040-6376",

publisher = "BMJ Publishing Group Ltd",

number = "6",

}

TY - JOUR

T1 - Exome-wide analysis of rare coding variation identifies novel associations with COPD and airflow limitation in MOCS3, IFIT3 and SERPINA12

AU - Jackson, Victoria E.

AU - Ntalla, Ioanna

AU - Sayers, Ian

AU - Morris, Richard

AU - Whincup, Peter

AU - Casas, Juan-Pablo

AU - Amuzu, Antoinette

AU - Choi, Minkyoung

AU - Dale, Caroline

AU - Kumari, Meena

AU - Engmann, Jorgen

AU - Kalsheker, Noor

AU - Chappell, Sally

AU - Guetta-Baranes, Tamar

AU - McKeever, Tricia M.

AU - Palmer, Colin N. A.

AU - Tavendale, Roger

AU - Holloway, John W.

AU - Sayer, Avan A.

AU - Dennison, Elaine M.

AU - Cooper, Cyrus

AU - Bafadhel, Mona

AU - Barker, Bethan

AU - Brightling, Chris

AU - Bolton, Charlotte E.

AU - John, Michelle E.

AU - Parker, Stuart G.

AU - Moffat, Miriam F.

AU - Wardlaw, Andrew J.

AU - Connolly, Martin J.

AU - Porteous, David J.

AU - Smith, Blair H.

AU - Padmanabhan, Sandosh

AU - Hocking, Lynne

AU - Stirrups, Kathleen E.

AU - Deloukas, Panos

AU - Strachan, David P.

AU - Hall, Ian P.

AU - Tobin, Martin D.

AU - Wain, Louise V.

N1 - Funding British Women’s Heart and Health Study is funded by the Department of Health grant no. 90049 and the British Heart Foundation grant no. PG/09/022. British Regional Heart Study is supported by the British Heart Foundation (grant RG/13/16/30528). CB (COPDBEAT) received funding from the Medical Research Council UK (grant no. G0601369), CB (COPDBEAT) and AJW (UKCOPD) were supported by the National Institute for Health Research (NIHR Leicester Biomedical Research Unit). MB (COPDBEAT) received funding from the NIHR (grant no. PDF-2013-06-052). Hertfordshire Cohort Study received support from the Medical Research Council, Arthritis Research UK, the International Osteoporosis Foundation and the British Heart Foundation; NIHR Biomedical Research Centre in Nutrition, University of Southampton; NIHR Musculoskeletal Biomedical Research Unit, University of Oxford. Generation Scotland: Scottish Family Health Study is funded by the Chief Scientist Office, Scottish Government Health Directorates, grant number CZD/16/6 and the Scottish Funding Council grant HR03006. EU COPD Gene Scan is funded by the European Union, grant no. QLG1-CT-2001-01012. English Longitudinal Study of Aging is funded by the Institute of Aging, NIH grant No. AG1764406S1. GoDARTs is funded by the Wellcome Trust grants 072960, 084726 and 104970. MDT has been supported by MRC fellowship G0902313. UK Biobank Lung Exome Variant Evaluation study was funded by a Medical Research Council strategic award to MDT, IPH, DPS and LVW (MC_PC_12010). Acknowledgements This research used the ALICE and SPECTRE High Performance Computing Facilities at the University of Leicester and was supported by the National Institute for Health Research (NIHR) Leicester Respiratory Biomedical Research Unit. This article/paper/report presents independent research funded partially by the NIHR. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. This research has been conducted using the UK Biobank Resource.

PY - 2016/6

Y1 - 2016/6

N2 - BACKGROUND: Several regions of the genome have shown to be associated with COPD in genome-wide association studies of common variants.OBJECTIVE: To determine rare and potentially functional single nucleotide polymorphisms (SNPs) associated with the risk of COPD and severity of airflow limitation.METHODS: 3226 current or former smokers of European ancestry with lung function measures indicative of Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2 COPD or worse were genotyped using an exome array. An analysis of risk of COPD was carried out using ever smoking controls (n=4784). Associations with %predicted FEV1 were tested in cases. We followed-up signals of interest (p<10(-5)) in independent samples from a subset of the UK Biobank population and also undertook a more powerful discovery study by meta-analysing the exome array data and UK Biobank data for variants represented on both arrays.RESULTS: Among the associated variants were two in regions previously unreported for COPD; a low frequency non-synonymous SNP in MOCS3 (rs7269297, pdiscovery=3.08×10(-6), preplication=0.019) and a rare SNP in IFIT3, which emerged in the meta-analysis (rs140549288, pmeta=8.56×10(-6)). In the meta-analysis of % predicted FEV1 in cases, the strongest association was shown for a splice variant in a previously unreported region, SERPINA12 (rs140198372, pmeta=5.72×10(-6)). We also confirmed previously reported associations with COPD risk at MMP12, HHIP, GPR126 and CHRNA5. No associations in novel regions reached a stringent exome-wide significance threshold (p<3.7×10(-7)).CONCLUSIONS: This study identified several associations with the risk of COPD and severity of airflow limitation, including novel regions MOCS3, IFIT3 and SERPINA12, which warrant further study.

AB - BACKGROUND: Several regions of the genome have shown to be associated with COPD in genome-wide association studies of common variants.OBJECTIVE: To determine rare and potentially functional single nucleotide polymorphisms (SNPs) associated with the risk of COPD and severity of airflow limitation.METHODS: 3226 current or former smokers of European ancestry with lung function measures indicative of Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2 COPD or worse were genotyped using an exome array. An analysis of risk of COPD was carried out using ever smoking controls (n=4784). Associations with %predicted FEV1 were tested in cases. We followed-up signals of interest (p<10(-5)) in independent samples from a subset of the UK Biobank population and also undertook a more powerful discovery study by meta-analysing the exome array data and UK Biobank data for variants represented on both arrays.RESULTS: Among the associated variants were two in regions previously unreported for COPD; a low frequency non-synonymous SNP in MOCS3 (rs7269297, pdiscovery=3.08×10(-6), preplication=0.019) and a rare SNP in IFIT3, which emerged in the meta-analysis (rs140549288, pmeta=8.56×10(-6)). In the meta-analysis of % predicted FEV1 in cases, the strongest association was shown for a splice variant in a previously unreported region, SERPINA12 (rs140198372, pmeta=5.72×10(-6)). We also confirmed previously reported associations with COPD risk at MMP12, HHIP, GPR126 and CHRNA5. No associations in novel regions reached a stringent exome-wide significance threshold (p<3.7×10(-7)).CONCLUSIONS: This study identified several associations with the risk of COPD and severity of airflow limitation, including novel regions MOCS3, IFIT3 and SERPINA12, which warrant further study.

U2 - 10.1136/thoraxjnl-2015-207876

DO - 10.1136/thoraxjnl-2015-207876

M3 - Article

C2 - 26917578

SN - 0040-6376

VL - 71

SP - 501

EP - 509

JO - Thorax

JF - Thorax

IS - 6

ER -

Exome-wide analysis of rare coding variation identifies novel associations with COPD and airflow limitation in MOCS3, IFIT3 and SERPINA12

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