Genetic loci associated with chronic obstructive pulmonary disease overlap with loci for lung function and pulmonary fibrosis

Abstract

Chronic obstructive pulmonary disease (COPD) is a leading cause of mortality worldwide. We performed a genetic association study in 15,256 cases and 47,936 controls, with replication of select top results (P < 5 × 10-6) in 9,498 cases and 9,748 controls. In the combined meta-analysis, we identified 22 loci associated at genome-wide significance, including 13 new associations with COPD. Nine of these 13 loci have been associated with lung function in general population samples, while 4 (EEFSEC, DSP, MTCL1, and SFTPD) are new. We noted two loci shared with pulmonary fibrosis (FAM13A and DSP) but that had opposite risk alleles for COPD. None of our loci overlapped with genome-wide associations for asthma, although one locus has been implicated in joint susceptibility to asthma and obesity. We also identified genetic correlation between COPD and asthma. Our findings highlight new loci associated with COPD, demonstrate the importance of specific loci associated with lung function to COPD, and identify potential regions of genetic overlap between COPD and other respiratory diseases.

Conflict of interest statement

Competing Financial Interest Statements:

I.P.H. has received grant support from Pfizer.

P.J.C. has received research funding from GSK.

B.P. serves on the DSMB of a clinical trial funded by the manufacturer and on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson.

N.L. and R.T-S. are shareholders and employees of GSK.

S.I.R. is a current employee and shareholder at AstraZeneca. He has served as a consultant, participated in advisory boards, received honorarium for speaking or grant support from: American Board of Internal Medicine, Advantage Healthcare, Almirall, American Thoracic Society, AstraZeneca, Baxter, Boehringer Ingelheim, Chiesi, ClearView Healthcare, Cleveland Clinic, Complete Medical Group, CSL, Dailchi Sankyo, Decision Resources, Forest, Gerson Lehman, Grifols, GroupH, Guidepoint Global, Haymarket, Huron Consulting, Inthought, Johnson and Johnson, Methodist Health System – Dallas, NCI Consulting, Novartis, Pearl, Penn Technology, Pfizer, PlanningShop, PSL FirstWord, Qwessential, Takeda, Theron and WebMD.

W.T. reports reports fees to the Department, all outside the submitted work, from Pfizer, GSK, Chiesi, Roche Diagnostics/Ventana, Biotest, Merck Sharp Dohme, Novartis, Lilly Oncology, Boehringer Ingelheim, and grants from Dutch Asthma Fund.

J.C.L. is currently an employee of GNS Healthcare in Cambridge, MA.

J.B.W. was employed by Pfizer during the time this research was performed.

P.B. has received consulting and lecture fees from AstraZeneca, Boehringer Ingelheim, Chiesi, Novartis, and Teva.

L.L. has performed consultancy for Boehringer Ingelheim GmbH, received an AstraZeneca Scientific Award and travel support from Novartis, European Respiratory Society, and the Belgian Respiratory Society.

P.G.W. has consulted for Amgen, Sanofi, Novartis, Genentech/Roche, Boehringer-Ingelheim, Neostem and has had research grants from Pfizer and Genentech.

D.L. received grant support, honoraria and consultancy fees from GSK for work on the ICGN and ECLIPSE studies, and was a member and then Chaired the GSK Respiratory Therapy Area Board (2009–2015).

M.H. is a current employee at AstraZeneca.

D.A.S. is serving on the scientific advisory boards of Apellis Pharmaceuticals and Pliant Therapeutics, and is the founder and owner of Eleven P15.

D.S.P. - The University of Groningen has received money for Professor Postma regarding a grant for research from Astra Zeneca, Chiesi, Genentec, GSK and Roche. Fees for consultancies were given to the University of Groningen by Astra Zeneca, Boehringer Ingelheim, Chiesi, GSK, Takeda and TEVA.

E.K.S. has received honoraria and consulting fees from Merck, grant support and consulting fees from GSK, and honoraria and travel support from Novartis.

M.H.C. has received grant support from GSK.

Figures

Figure 1

Study design showing cohorts used in each stage of the analysis. ARIC = Atherosclerosis Risk in Communities Study, B58 = British 1958 Birth Cohort, CHS = Cardiovascular Health Study, COPACETIC = COPD Pathology: Addressing Critical gaps, Early Treatment & Diagnosis and Innovative Concepts, ECLIPSE = Evaluation of COPD Longitudinally to Identify Predictive Surrogate End-points, eQTL = Lung Expression Quantitative Trait Loci Study, FHS = Framingham Heart Study, KARE = Korean Association Resource project, MESA = Multi-Ethnic Study of Atherosclerosis, NETT-NAS = National Emphysema Treatment Trial/Normative Aging Study, RS = Rotterdam Study, SPIROMICS = Subpopulations and intermediate outcome measures in COPD study, EOCOPD = Boston Early-Onset COPD Study, ICGN = International COPD Genetics Network, TCGS = Transcontinental COPD Genetics Study, UK BiLEVE = UK Biobank Lung Exome Variant Evaluation; NHW = Non-Hispanic white, AA = African American, EA = European American. * Studies without genome-wide array genotyping (custom genotyping)

Figure 2

Manhattan plot showing P values for Stage 1 analysis (small open diamonds) with overlay of overall meta-analysis P values for SNPs analyzed in UK BiLEVE Stage 2 analysis (filled circles). Gene names in gray are previously described COPD or lung function (FEV1 or FEV1/FVC) loci; black are novel loci discovered in this study. The Stage 1 cohorts with available genotyping data (Supplementary Figures 1a–v) and the UK BiLEVE cohort determined the sample size for each top variant. The red dashed line indicates the threshold for genome-wide significance (P value < 5×10−8).

Figure 3. a–d Regional association for novel loci

LocusZoom plots showing regional association of variants at the four novel COPD loci. The point size is proportional to the sample size, where Stage 1 cohorts with available genotyping data (Supplementary Figures 1a–v) and the UK BiLEVE cohort determined the sample size for each top variant.

Figure 4. Genetic correlation (using LD score regression) between COPD and other traits

Shading and numbers represents strength of correlation. An asterisk indicates nominal (P 1 from CHARGE/SpiroMeta, asthma taken from the asthma GWAS by the GABRIEL Consortium, ild = pulmonary fibrosis from Fingerlin et al.,, bilSmk = subset of smokers in the UK BiLEVE study, smkCpd = cigarettes per day smoking from the Tobacco and Genetics (TAG) Consortium, smkFormer = current versus former smokers from TAG, smkOnset = age of smoking initiation from TAG, smkEver = ever versus never smoking from TAG. cad = coronary artery disease from the CARDIoGRAM study, height and bmi (body mass index) from the GIANT consortium, bmdLumbar and bmdFemoral = lumbar and femoral bone mineral density, respectively, from the Genetic Factors for Osteoporosis (GeFOS) Consortium.