Multiethnic meta-analysis identifies ancestry-specific and cross-ancestry loci for pulmonary function
Wyss AB, Sofer T, Lee MK, Terzikhan N, Nguyen JN, Lahousse L, Latourelle JC, Smith AV, Bartz TM, Feitosa MF, Gao W, Ahluwalia TS, Tang W, Oldmeadow C, Duan Q, de Jong K, Wojczynski MK, Wang XQ, Noordam R, Hartwig FP, Jackson VE, Wang T, Obeidat M, Hobbs BD, Huan T, Gui H, Parker MM, Hu D, Mogil LS, Kichaev G, Jin J, Graff M, Harris TB, Kalhan R, Heckbert SR, Paternoster L, Burkart KM, Liu Y, Holliday EG, Wilson JG, Vonk JM, Sanders JL, Barr RG, de Mutsert R, Menezes AMB, Adams HHH, van den Berge M, Joehanes R, Levin AM, Liberto J, Launer LJ, Morrison AC, Sitlani CM, Celedon JC, Kritchevsky SB, Scott RJ, Christensen K, Rotter JI, Bonten TN, Wehrmeister FC, Bosse Y, Xiao S, Oh S, Franceschini N, Brody JA, Kaplan RC, Lohman K, McEvoy M, Province MA, Rosendaal FR, Taylor KD, Nickle DC, Williams LK, Burchard EG, Wheeler HE, Sin DD, Gudnason V, North KE, Fornage M, Psaty BM, Myers RH, O'Connor G, Hansen T, Laurie CC, Cassano PA, Sung J, Kim WJ, Attia JR, Lange L, Boezen HM, Thyagarajan B, Rich SS, Mook-Kanamori DO, Horta BL, Uitterlinden AG, Im HK, Cho MH, Brusselle GG, Gharib SA, Dupuis J, Manichaikul A, and London SJ. Multiethnic meta-analysis identifies ancestry-specific and cross-ancestry loci for pulmonary function. Nat Commun 2018; 9(1):2976.
Nearly 100 loci have been identified for pulmonary function, almost exclusively in studies of European ancestry populations. We extend previous research by meta-analyzing genome-wide association studies of 1000 Genomes imputed variants in relation to pulmonary function in a multiethnic population of 90,715 individuals of European (N = 60,552), African (N = 8429), Asian (N = 9959), and Hispanic/Latino (N = 11,775) ethnicities. We identify over 50 additional loci at genome-wide significance in ancestry-specific or multiethnic meta-analyses. Using recent fine-mapping methods incorporating functional annotation, gene expression, and differences in linkage disequilibrium between ethnicities, we further shed light on potential causal variants and genes at known and newly identified loci. Several of the novel genes encode proteins with predicted or established drug targets, including KCNK2 and CDK12. Our study highlights the utility of multiethnic and integrative genomics approaches to extend existing knowledge of the genetics of lung function and clinical relevance of implicated loci.
Medical Subject Headings
African Continental Ancestry Group; Asian Americans; European Continental Ancestry Group; Female; Forced Expiratory Volume; Genetic Predisposition to Disease; Genome-Wide Association Study; Genomics; Hispanic Americans; Humans; Linkage Disequilibrium; Lung; Lung Diseases; Male; Polymorphism, Single Nucleotide; Pulmonary Disease, Chronic Obstructive; Quantitative Trait Loci; Regression Analysis; Sample Size; Smoking; Vital Capacity