Reduced lung function predicts mortality and is key to the diagnosis of chronic obstructive pulmonary disease (COPD). In a genome-wide association study in 400,102 individuals of European ancestry, we define 279 lung function signals, 139 of which are new. In combination, these variants strongly predict COPD in independent patient populations. Furthermore, the combined effect of these variants showed generalizability across smokers and never-smokers, and across ancestral groups. We highlight biological pathways, known and potential drug targets for COPD and, in phenome-wide association studies, autoimmune-related and other pleiotropic effects of lung function associated variants. This new genetic evidence has potential to improve future preventive and therapeutic strategies for COPD.

Chronic Obstructive Pulmonary Disease (COPD) is characterised 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 ratios per standard deviation of the risk score (~6 alleles) (95% confidence interval) 1.24 (1.20-1.27), P=5.05x10-49) and we observed a 3.7 fold difference in COPD risk between highest and lowest genetic risk score deciles in UK Biobank. The 97 signals show enrichment in development, elastic fibres 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.

Identification of obstructive sleep apnea and risk factors is important for reduction in symptoms and cardiovascular risk, and for improvement of quality of life. The population‐based Study of Health in Pomerania investigated risk factors and clinical diseases in a general population of northeast Germany. Additional polysomnography was applied to measure sleep and respiration with the objective of assessing prevalence and risk factors of obstructive sleep apnea in a German cohort. One‐thousand, two‐hundred and eight people between 20 and 81 years old (54% men, median age 54 years) underwent overnight polysomnography. The estimated obstructive sleep apnea prevalence was 46% (59% men, 33% women) for an apnea–hypopnea index ≥5%, and 21% (30% men, 13% women) for an apnea–hypopnea index ≥ 15. The estimated obstructive sleep apnea syndrome prevalence (apnea–hypopnea index ≥5; Epworth Sleepiness Scale >10) was 6%. The prevalence of obstructive sleep apnea continuously increased with age for men and women with, however, later onset for women. Gender, age, body mass index, waist‐to‐hip ratio, snoring, alcohol consumption (for women only) and self‐reported cardiovascular diseases were significantly positively associated with obstructive sleep apnea, whereas daytime sleepiness was not. Diabetes, hypertension and metabolic syndrome were positively associated with severe obstructive sleep apnea. The associations became non‐significant after adjustment for body mass. Women exhibited stronger associations than men. The prevalence of obstructive sleep apnea was high, with almost half the population presenting some kind of obstructive sleep apnea. The continuous increase of obstructive sleep apnea with age challenges the current theory that mortality due to obstructive sleep apnea and cardiovascular co‐morbidities affect obstructive sleep apnea prevalence at an advanced age. Also, gender differences regarding obstructive sleep apnea and associations are significant for recognizing obstructive sleep apnea mechanisms and therapy responsiveness.

Lung function measures are used in the diagnosis of chronic obstructive pulmonary disease. In 38,199 European ancestry individuals, we studied genome-wide association of forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC) and FEV1/FVC with 1000 Genomes Project (phase 1)-imputed genotypes and followed up top associations in 54,550 Europeans. We identify 14 novel loci (P<5 × 10−8) in or near ENSA, RNU5F-1, KCNS3, AK097794, ASTN2, LHX3, CCDC91, TBX3, TRIP11, RIN3, TEKT5, LTBP4, MN1 and AP1S2, and two novel signals at known loci NPNT and GPR126, providing a basis for new understanding of the genetic determinants of these traits and pulmonary diseases in which they are altered.

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