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

Jackson, Victoria E and Ntalla, Ioanna and Sayers, Ian and Morris, Richard and Whincup, Peter and Casas, Juan-Pablo and Amuzu, Antoinette and Choi, Minkyoung and Dale, Caroline and Kumari, Meena and Engmann, Jorgen and Kalsheker, Noor and Chappell, Sally and Guetta-Baranes, Tamar and McKeever, Tricia M and Palmer, Colin NA and Tavendale, Roger and Holloway, John W and Sayer, Avan A and Dennison, Elaine M and Cooper, Cyrus and Bafadhel, Mona and Barker, Bethan and Brightling, Chris 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 Padmanabhan, Sandosh and Hocking, Lynne and Stirrups, Kathleen E and Deloukas, Panos and Strachan, David P and Hall, Ian P and Tobin, Martin D and Wain, Louise V (2016) 'Exome-wide analysis of rare coding variation identifies novel associations with COPD and airflow limitation in<i>MOCS3</i>,<i>IFIT3</i>and<i>SERPINA12</i>.' Thorax, 71 (6). pp. 501-509. ISSN 0040-6376

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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 metaanalysing 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.

Item Type: Article
Uncontrolled Keywords: Humans; Pulmonary Disease, Chronic Obstructive; Airway Obstruction; Nucleotidyltransferases; Sulfurtransferases; Intracellular Signaling Peptides and Proteins; Serpins; Forced Expiratory Volume; Risk Assessment; Smoking; Genotype; Polymorphism, Single Nucleotide; Aged; Middle Aged; Female; Male; Genome-Wide Association Study; Exome
Subjects: H Social Sciences > H Social Sciences (General)
R Medicine > R Medicine (General)
Divisions: Faculty of Social Sciences
Faculty of Social Sciences > Institute for Social and Economic Research
SWORD Depositor: Elements
Depositing User: Elements
Date Deposited: 21 Jun 2016 14:33
Last Modified: 11 Apr 2022 20:49
URI: http://repository.essex.ac.uk/id/eprint/16979

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