Exome-wide analysis of rare coding variation identifies novel associations with COPD and airflow limitation inMOCS3,IFIT3andSERPINA12

Abstract

BackgroundSeveral regions of the genome have shown to be associated with COPD in genome-wide association studies of common variants.ObjectiveTo determine rare and potentially functional single nucleotide polymorphisms (SNPs) associated with the risk of COPD and severity of airflow limitation.Methods3226 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.ResultsAmong 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).ConclusionsThis 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.

Rare variant of MAP2K7 is associated with increased risk of COPD in southern and eastern Chinese

“…For example, one previous study investigated the association between genetic variants in the coding regions of the CHRNA3‐CHRNA5‐CHRNB4 genes and COPD risk in Chinese using direct exon sequencing and found that three rare missense variations contributed to increased risk of COPD and worsen lung functions . In addition, other evidence showed a newfound low frequency non‐synonymous SNP in MOCS3 and a rare variant in IFIT3 to be associated with the risk of COPD and severity of airflow limitation . In our study, we observed a significant link of p.Glu116Lys rare variant in MAP2K7 to COPD risk and found that this rare variant could explain about 1.92% of COPD heritability.…”

“…31 In addition, other evidence showed a newfound low frequency non-synonymous SNP in MOCS3 and a rare variant in IFIT3 to be associated with the risk of COPD and severity of airflow limitation. 29 In our study, we observed a significant link of p.Glu116Lys rare variant in MAP2K7 to COPD risk and found that this rare variant could explain about 1.92% of COPD heritability. All the above suggested that p.Glu116Lys rare variant in MAP2K7 might be a genetic marker for COPD susceptibility.…”

“…In the past a few years, previously neglected genetic components such as low frequency or rare genetic variants, have been gradually uncovered with high‐throughput sequencing technologies. These variants are also being assessed and investigated in their relevance to complex diseases, including COPD . Evidence indicated that rare variants might be able to explain the additional heritable components of disease commendably better than common variants can .…”

“…These variants are also being assessed and investigated in their relevance to complex diseases, including COPD. 10,11,28,29 Evidence indicated that rare variants might be able to explain the additional heritable components of disease commendably better than common variants can. 30 For example, one previous study investigated the association between genetic variants in the coding regions of the CHRNA3-CHRNA5-CHRNB4 genes and COPD risk in Chinese using direct exon sequencing and found that three rare missense variations contributed to increased risk of COPD and worsen lung functions.…”

Genetic Association and Risk Scores in a Chronic Obstructive Pulmonary Disease Meta-analysis of 16,707 Subjects

“…Four of the datasets in our metaanalysis were previously investigated for genetic associations for COPD status (18), so our results are enriched for previously discovered associations. In addition, genotyping was performed before the results of recent COPD and lung function GWAS studies by the UK BiLEVE group (7) and Soler Artigas and colleagues (57,58) were published, and the additional risk loci for COPD and lung function found in these studies were not included in our analysis. We chose to use a simple model for our genetic (and clinical) risk scores.…”