Pulmonary function is an easily measurable and reliable index of the physiological state of the lungs and airways 1 . Pulmonary function also predicts mortality in the general population, even among people who have never smoked (never-smokers) who have only modestly reduced pulmonary function and no respiratory symptoms 2,3 . The peak level of pulmonary function attained in early adulthood and its subsequent decline with age are likely influenced by genetic and environmental factors. Tobacco smoking is a major environmental cause of accelerated decline in pulmonary function with age. Other inhaled pollutants also appear to contribute. Familial aggregation studies suggest a genetic contribution to lung function, with heritability estimates exceeding 40% 4,5 , but little is known about the specific genetic factors involved. A relatively uncommon deficiency of α1-antitrypsin is the only established genetic risk factor for accelerated decline in pulmonary function and for development of chronic obstructive pulmonary disease (COPD), especially in smokers 4,6 . However, α1-antitrypsin accounts for little of the population variability in pulmonary function 4 . Candidate gene studies suggest that other genetic variants may influence the time course of pulmonary function and its decline in relation to smoking, but these putative genetic risk factors remain unknown 4 .Forced expiratory volume in the first second (FEV 1 ) and its ratio to forced vital capacity (FEV 1 /FVC) are two clinically relevant pulmonary function measures. Although both FEV 1 and FVC are influenced by lung size and can be reduced by restrictive lung diseases, obstructive lung disease leads to proportionately greater reduction in FEV 1 than FVC. Therefore, reduced FEV 1 /FVC, an indicator of airflow obstruction that is independent of lung size, is the primary criterion for defining an obstructive ventilatory defect 1 . Whereas low FEV 1 /FVC indicates the presence of airflow obstruction, FEV 1 is used to classify the severity and follow the progression of obstructive lung disease over time 5,7,8 .The first genome-wide association study (GWAS) for pulmonary function evaluating 70,987 SNPs in about 1,220 Framingham Heart Study (FHS) participants revealed no genome-wide significant loci 9 . Recently, a GWAS of FEV 1 /FVC using 2,540,223 SNPs in 7,691 FHS participants identified several SNPs on chromosome 4q31 near HHIP with genome-wide significance 10 . A GWAS of COPD 11 also implicated the HHIP region along with CHRNA3-CHRNA5 on chromosome 15, a region previously associated with nicotine dependence 12,13 .We conducted meta-analyses of GWAS results for a cross-sectional analysis of pulmonary function (FEV 1 /FVC and FEV 1 ) in 20,890 individuals of European ancestry from four Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium 14 studies: Atherosclerosis Risk in Communities (ARIC), Cardiovascular Health Study (CHS), FHS and Rotterdam Study (RS-I and RS-II). Given that cigarette smoking is a major risk factor for pulmonary fun...

Liability to alcohol dependence (AD) is heritable, but little is known about its complex polygenic architecture or its genetic relationship with other disorders. To discover loci associated with AD and characterize the relationship between AD and other psychiatric and behavioral outcomes, we carried out the largest GWAS to date of DSM-IV diagnosed AD. Genome-wide data on 14,904 individuals with AD and 37,944 controls from 28 case/control and family-based studies were meta-analyzed, stratified by genetic ancestry (European, N = 46,568; African; N = 6,280). Independent, genome-wide significant effects of different ADH1B variants were identified in European (rs1229984; p = 9.8E-13) and African ancestries (rs2066702; p = 2.2E-9). Significant genetic correlations were observed with 17 phenotypes, including schizophrenia, ADHD, depression, and use of cigarettes and cannabis. The genetic underpinnings of AD only partially overlap with those for alcohol consumption, underscoring the genetic distinction between pathological and non-pathological drinking behaviors.

SummaryWhile several lung cancer susceptibility loci have been identified, much of lung cancer heritability remains unexplained. Here, 14,803 cases and 12,262 controls of European descent were genotyped on the OncoArray and combined with existing data for an aggregated GWAS analysis of lung cancer on 29,266 patients and 56,450 controls. We identified 18 susceptibility loci achieving genome wide significance, including 10 novel loci. The novel loci highlighted the striking heterogeneity in genetic susceptibility across lung cancer histological subtypes, with four loci associated with lung cancer overall and six with lung adenocarcinoma. Gene expression quantitative trait analysis (eQTL) in 1,425 normal lung tissues highlighted RNASET2, SECISBP2L and NRG1 as candidate genes. Other loci include genes such as a cholinergic nicotinic receptor, CHRNA2, and the telomere-related genes, OFBC1 and RTEL1. Further exploration of the target genes will continue to provide new insights into the etiology of lung cancer.

Pulmonary function measures reflect respiratory health and predict mortality, and are used in the diagnosis of chronic obstructive pulmonary disease (COPD). We tested genome-wide association with the forced expiratory volume in 1 second (FEV1) and the ratio of FEV1 to forced vital capacity (FVC) in 48,201 individuals of European ancestry, with follow-up of top associations in up to an additional 46,411 individuals. We identified new regions showing association (combined P<5×10−8) with pulmonary function, in or near MFAP2, TGFB2, HDAC4, RARB, MECOM (EVI1), SPATA9, ARMC2, NCR3, ZKSCAN3, CDC123, C10orf11, LRP1, CCDC38, MMP15, CFDP1, and KCNE2. Identification of these 16 new loci may provide insight into the molecular mechanisms regulating pulmonary function and into molecular targets for future therapy to alleviate reduced lung function.