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.
Bibliographical noteFunding Information:
We thank the International COPD Genetics Consortium (members listed in Supplementary Note 3) for investigating overlap of newly identified lung function loci with COPD in their study. We also thank Huiling Li for expert technical assistance and Dr. Frank Day for computational support, both from the National Institute of Environmental Health Sciences (NIEHS), and Dr. Louise Wain, University of Leicester, for critical reviews of the manuscript. Supported in part by the Intramural Research Program of the National Institutes of Health, NIEHS. Infrastructure for the CHARGE Consortium is supported in part by the National Heart, Lung, and Blood Institute Grant R01HL105756. Study-specific funding and acknowledgments can be found in Supplementary Note 3.
Competing interests: J.C.L. is currently an employee of GNS Healthcare. W.T. is currently an employee of Boehringer Ingelheim Pharmaceuticals. A.M.B.M. has received grant support from GlaxoSmithKline and from AstraZeneca in the last 5 years, but not for the present study. J.C.C. received research materials from Pharmavite (vitamin D and placebo capsules), GSK (Flovent), and Merck (Asmanex) to provide medications free of cost to participants in NIH-funded studies. D.C.N. is an employee of Merck Research Laboratories. D.D.S. has received research funding from Boehringer Ingelheim, Merck, and AstraZeneca outside the scope of this work. B.M.P. serves on the DSMB of a clinical trial funded by the manufacturer (Zoll LifeCor) and on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson. M.H.C. has received grant support from GlaxoSmithKline. The authors declare no other competing interests.