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

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

Abstract / Description of output

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
Journal	Thorax
Early online date	25 Feb 2016
DOIs	https://doi.org/10.1136/thoraxjnl-2015-207876
Publication status	E-pub ahead of print - 25 Feb 2016

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10.1136/thoraxjnl-2015-207876

Porteous D Exome-wide analysis
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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. Advance online publication. 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 = "Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/",

year = "2016",

month = feb,

day = "25",

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

language = "English",

journal = "Thorax",

issn = "0040-6376",

publisher = "BMJ Publishing Group",

}

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. https://doi.org/10.1136/thoraxjnl-2015-207876

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 - Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

PY - 2016/2/25

Y1 - 2016/2/25

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

JO - Thorax

JF - Thorax

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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