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

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 FEV(1) 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, p(discovery)=3.08×10(−6), p(replication)=0.019) and a rare SNP in IFIT3, which emerged in the meta-analysis (rs140549288, p(meta)=8.56×10(−6)). In the meta-analysis of % predicted FEV(1) in cases, the strongest association was shown for a splice variant in a previously unreported region, SERPINA12 (rs140198372, p(meta)=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.