| Title: | Exome-wide analysis of rare coding variation identifies novel associations with COPD and airflow limitation in MOCS3, IFIT3 and SERPINA12 |
| Journal: | Thorax |
| Published: | 25 Feb 2016 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/26917578/ |
| DOI: | https://doi.org/10.1136/thoraxjnl-2015-207876 |
| URL: | https://thorax.bmj.com/content/thoraxjnl/71/6/501.full.pdf |
Publication 8420
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Abstract
BACKGROUND: Several regions of the genome have shown to be associated with COPD in genome-wide association studies of common variants.</p>
OBJECTIVE: To determine rare and potentially functional single nucleotide polymorphisms (SNPs) associated with the risk of COPD and severity of airflow limitation.</p>
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.</p>
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)).</p>
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.</p>
40 Authors
- Victoria E Jackson
- Ioanna Ntalla
- Ian Sayers
- Richard Morris
- Peter Whincup
- Juan-Pablo Casas
- Antoinette Amuzu
- Minkyoung Choi
- Caroline Dale
- Meena Kumari
- Jorgen Engmann
- Noor Kalsheker
- Sally Chappell
- Tamar Guetta-Baranes
- Tricia M McKeever
- Colin N A Palmer
- Roger Tavendale
- John W Holloway
- Avan A Sayer
- Elaine M Dennison
- Cyrus Cooper
- Mona Bafadhel
- Bethan Barker
- Chris Brightling
- Charlotte E Bolton
- Michelle E John
- Stuart G Parker
- Miriam F Moffat
- Andrew J Wardlaw
- Martin J Connolly
- David J Porteous
- Blair H Smith
- Sandosh Padmanabhan
- Lynne Hocking
- Kathleen E Stirrups
- Panos Deloukas
- David P Strachan
- Ian P Hall
- Martin D Tobin
- Louise V Wain
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