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Exome-wide analysis of rare coding variation identifies novel associations with COPD and airflow limitation in
Lookup NU author(s)
Professor Avan Aihie Sayer
Professor Stuart Parker
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
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Several regions of the genome have shown to be associated with COPD in genome-wide association studies of common variants.
To determine rare and potentially functional single nucleotide polymorphisms (SNPs) associated with the risk of COPD and severity of airflow limitation.
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 FEV
were tested in cases. We followed-up signals of interest (p<10
) 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.
Among the associated variants were two in regions previously unreported for COPD; a low frequency non-synonymous SNP in
=0.019) and a rare SNP in
, which emerged in the meta-analysis (rs140549288, p
). In the meta-analysis of % predicted FEV
in cases, the strongest association was shown for a splice variant in a previously unreported region,
). We also confirmed previously reported associations with COPD risk at
. No associations in novel regions reached a stringent exome-wide significance threshold (p<3.7×10
This study identified several associations with the risk of COPD and severity of airflow limitation, including novel regions
, which warrant further study.
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