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.