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 W Morris, P Whincup, JP Casas, Antoinette Amuzu, Minkyoung Choi, Caroline Dale, Meena Kumari, Jorgen E L Engmann, Noor Kalsheker, Sally Chappell, Tamar Guetta-Baranes, Tricia McKeever, Colin N A Palmer, Roger Tavendale, John W Holloway, Avan Aihie Sayer, Elaine DennisonCyrus Cooper, Mona Bafadhel, Bethan Barker, Chris Brightling, Charlotte E Bolton, Michelle E John, S Parker, Miriam F Moffatt, AJ Wardlaw, M Connolly, DJ Porteous, Blair Smith, Sandosh Padmanabhan, Lynne Hocking, Kathleen Stirrups, P Deloukas, David P Strachan, Ian P Hall, Martin D Tobin, Louise V Wain

Research output: Contribution to journalArticle (Academic Journal)peer-review

15 Citations (Scopus)
222 Downloads (Pure)


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 languageEnglish
Pages (from-to)501-509
Number of pages9
Issue number6
Early online date25 Feb 2016
Publication statusPublished - Jun 2016

Fingerprint Dive into the research topics of '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>'. Together they form a unique fingerprint.

Cite this