Genome-wide association analyses for lung function and chronic obstructive pulmonary disease identify new loci and potential druggable targets.
Nature genetics 2016 ; 49: 416-425.
Wain LV, Shrine N, Artigas MS, Erzurumluoglu AM, Noyvert B, Bossini-Castillo L, Obeidat M, Henry AP, Portelli MA, Hall RJ, Billington CK, Rimington TL, Fenech AG, John C, Blake T, Jackson VE, Allen RJ, Prins BP, Understanding Society Scientific Group, Campbell A, Porteous DJ, Järvelin MR, Wielscher M, James AL, Hui J, Wareham NJ, Zhao JH, Wilson JF, Joshi PK, Stubbe B, Rawal R, Schulz H, Imboden M, Probst-Hensch NM, Karrasch S, Gieger C, Deary IJ, Harris SE, Marten J, Rudan I, Enroth S, Gyllensten U, Kerr SM, Polasek O, Kähönen M, Surakka I, Vitart V, Hayward C, Lehtimäki T, Raitakari OT, Evans DM, Henderson AJ, Pennell CE, Wang CA, Sly PD, Wan ES, Busch R, Hobbs BD, Litonjua AA, Sparrow DW, Gulsvik A, Bakke PS, Crapo JD, Beaty TH, Hansel NN, Mathias RA, Ruczinski I, Barnes KC, Bossé Y, Joubert P, Van den Berge M, Brandsma CA, Paré PD, Sin DD, Nickle DC, Hao K, Gottesman O, Dewey FE, Bruse SE, Carey DJ, Kirchner HL, Geisinger-Regeneron DiscovEHR Collaboration Geisinger-Regeneron DiscovEHR Collaboration, Jonsson S, Thorleifsson G, Jonsdottir I, Gislason T, Stefansson K, Schurmann C, Nadkarni G, Bottinger EP, Loos RJ, Walters RG, Chen Z, Millwood IY, Vaucher J, Kurmi OP, Li L, Hansell AL, Brightling C, Zeggini E, Cho MH, Silverman EK, Sayers I, Trynka G, Morris AP, Strachan DP, Hall IP, and Tobin MD
DOI : 10.1038/ng.3787
PubMed ID : 28166213
PMCID : PMC5326681
Chronic obstructive pulmonary disease (COPD) is characterized by reduced lung function and is the third leading cause of death globally. Through genome-wide association discovery in 48,943 individuals, selected from extremes of the lung function distribution in UK Biobank, and follow-up in 95,375 individuals, we increased the yield of independent signals for lung function from 54 to 97. A genetic risk score was associated with COPD susceptibility (odds ratio per 1 s.d. of the risk score (∼6 alleles) (95% confidence interval) = 1.24 (1.20-1.27), P = 5.05 × 10), and we observed a 3.7-fold difference in COPD risk between individuals in the highest and lowest genetic risk score deciles in UK Biobank. The 97 signals show enrichment in genes for development, elastic fibers and epigenetic regulation pathways. We highlight targets for drugs and compounds in development for COPD and asthma (genes in the inositol phosphate metabolism pathway and CHRM3) and describe targets for potential drug repositioning from other clinical indications.