Genome-wide association study of preserved ratio impaired spirometry (PRISm)

Author:

Higbee Daniel H.,Lirio Alvin,Hamilton Fergus,Granell Raquel,Wyss Annah B.,London Stephanie J.ORCID,Bartz Traci M.,Gharib Sina A.ORCID,Cho Michael H.ORCID,Wan EmilyORCID,Silverman Edwin,Crapo James D.,Lominchar Jesus V.T.,Hansen Torben,Grarup Niels,Dantoft Thomas,Kårhus Line,Linneberg Allan,O'Connor George T.,Dupuis Josée,Xu Hanfie,De Vries Maaike M.ORCID,Hu Xiaowei,Rich Stephen S.ORCID,Barr R. Graham,Manichaikul Ani,Wijnant Sara R.A.ORCID,Brusselle Guy G.ORCID,Lahousse LiesORCID,Li Xuan,Hernández Cordero Ana I.ORCID,Obeidat Ma'en,Sin Don D.,Harris Sarah E.,Redmond Paul,Taylor Adele M.,Cox Simon R.,Williams Alexander T.,Shrine NickORCID,John Catherine,Guyatt Anna L.ORCID,Hall Ian P.,Davey Smith GeorgeORCID,Tobin Martin D.ORCID,Dodd James W.ORCID

Abstract

BackgroundPreserved ratio impaired spirometry (PRISm) is defined as a forced expiratory volume in 1 s (FEV1) <80% predicted and FEV1/forced vital capacity ≥0.70. PRISm is associated with respiratory symptoms and comorbidities. Our objective was to discover novel genetic signals for PRISm and see if they provide insight into the pathogenesis of PRISm and associated comorbidities.MethodsWe undertook a genome-wide association study (GWAS) of PRISm in UK Biobank participants (Stage 1), and selected single nucleotide polymorphisms (SNPs) reaching genome-wide significance for replication in 13 cohorts (Stage 2). A combined meta-analysis of Stage 1 and Stage 2 was done to determine top SNPs. We used cross-trait linkage disequilibrium score regression to estimate genome-wide genetic correlation between PRISm and pulmonary and extrapulmonary traits. Phenome-wide association studies of top SNPs were performed.Results22 signals reached significance in the joint meta-analysis, including four signals novel for lung function. A strong genome-wide genetic correlation (rg) between PRISm and spirometric COPD (rg=0.62, p<0.001) was observed, and genetic correlation with type 2 diabetes (rg=0.12, p=0.007). Phenome-wide association studies showed that 18 of 22 signals were associated with diabetic traits and seven with blood pressure traits.ConclusionThis is the first GWAS to successfully identify SNPs associated with PRISm. Four of the signals, rs7652391 (nearest geneMECOM), rs9431040 (HLX), rs62018863 (TMEM114) and rs185937162 (HLA-B), have not been described in association with lung function before, demonstrating the utility of using different lung function phenotypes in GWAS. Genetic factors associated with PRISm are strongly correlated with risk of both other lung diseases and extrapulmonary comorbidity.

Funder

Center for Strategic Scientific Initiatives, National Cancer Institute

National Institute of Environmental Health Sciences

European Commission

Medical Research Council

Novo Nordisk

Science to Achieve Results

Nederlandse Organisatie voor Wetenschappelijk Onderzoek

Wellcome Trust

National Heart, Lung, and Blood Institute

American Recovery and Reinvestment Act

Biotechnology and Biological Sciences Research Council

Economic and Social Research Council

Funds for Scientific Research Flanders

Publisher

European Respiratory Society (ERS)

Subject

Pulmonary and Respiratory Medicine

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