RT Journal Article SR Electronic T1 Exome-wide analysis of rare coding variation identifies novel associations with COPD and airflow limitation in MOCS3, IFIT3 and SERPINA12 JF Thorax JO Thorax FD BMJ Publishing Group Ltd and British Thoracic Society SP 501 OP 509 DO 10.1136/thoraxjnl-2015-207876 VO 71 IS 6 A1 Victoria E Jackson A1 Ioanna Ntalla A1 Ian Sayers A1 Richard Morris A1 Peter Whincup A1 Juan-Pablo Casas A1 Antoinette Amuzu A1 Minkyoung Choi A1 Caroline Dale A1 Meena Kumari A1 Jorgen Engmann A1 Noor Kalsheker A1 Sally Chappell A1 Tamar Guetta-Baranes A1 Tricia M McKeever A1 Colin N A Palmer A1 Roger Tavendale A1 John W Holloway A1 Avan A Sayer A1 Elaine M Dennison A1 Cyrus Cooper A1 Mona Bafadhel A1 Bethan Barker A1 Chris Brightling A1 Charlotte E Bolton A1 Michelle E John A1 Stuart G Parker A1 Miriam F Moffat A1 Andrew J Wardlaw A1 Martin J Connolly A1 David J Porteous A1 Blair H Smith A1 Sandosh Padmanabhan A1 Lynne Hocking A1 Kathleen E Stirrups A1 Panos Deloukas A1 David P Strachan A1 Ian P Hall A1 Martin D Tobin A1 Louise V Wain YR 2016 UL http://thorax.bmj.com/content/71/6/501.abstract 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.