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Large-scale genome-wide association studies and meta-analyses of longitudinal change in adult lung function.

ABSTRACT: BACKGROUND:Genome-wide association studies (GWAS) have identified numerous loci influencing cross-sectional lung function, but less is known about genes influencing longitudinal change in lung function. METHODS:We performed GWAS of the rate of change in forced expiratory volume in the first second (FEV1) in 14 longitudinal, population-based cohort studies comprising 27,249 adults of European ancestry using linear mixed effects model and combined cohort-specific results using fixed effect meta-analysis to identify novel genetic loci associated with longitudinal change in lung function. Gene expression analyses were subsequently performed for identified genetic loci. As a secondary aim, we estimated the mean rate of decline in FEV1 by smoking pattern, irrespective of genotypes, across these 14 studies using meta-analysis. RESULTS:The overall meta-analysis produced suggestive evidence for association at the novel IL16/STARD5/TMC3 locus on chromosome 15 (P ?=? 5.71 × 10(-7)). In addition, meta-analysis using the five cohorts with ?3 FEV1 measurements per participant identified the novel ME3 locus on chromosome 11 (P ?=? 2.18 × 10(-8)) at genome-wide significance. Neither locus was associated with FEV1 decline in two additional cohort studies. We confirmed gene expression of IL16, STARD5, and ME3 in multiple lung tissues. Publicly available microarray data confirmed differential expression of all three genes in lung samples from COPD patients compared with controls. Irrespective of genotypes, the combined estimate for FEV1 decline was 26.9, 29.2 and 35.7 mL/year in never, former, and persistent smokers, respectively. CONCLUSIONS:In this large-scale GWAS, we identified two novel genetic loci in association with the rate of change in FEV1 that harbor candidate genes with biologically plausible functional links to lung function.

SUBMITTER: Tang W

PROVIDER: S-EPMC4077649 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Large-scale genome-wide association studies and meta-analyses of longitudinal change in adult lung function.

Tang Wenbo W Kowgier Matthew M Loth Daan W DW Soler Artigas María M Joubert Bonnie R BR Hodge Emily E Gharib Sina A SA Smith Albert V AV Ruczinski Ingo I Gudnason Vilmundur V Mathias Rasika A RA Harris Tamara B TB Hansel Nadia N NN Launer Lenore J LJ Barnes Kathleen C KC Hansen Joyanna G JG Albrecht Eva E Aldrich Melinda C MC Allerhand Michael M Barr R Graham RG Brusselle Guy G GG Couper David J DJ Curjuric Ivan I Davies Gail G Deary Ian J IJ Dupuis Josée J Fall Tove T Foy Millennia M Franceschini Nora N Gao Wei W Gläser Sven S Gu Xiangjun X Hancock Dana B DB Heinrich Joachim J Hofman Albert A Imboden Medea M Ingelsson Erik E James Alan A Karrasch Stefan S Koch Beate B Kritchevsky Stephen B SB Kumar Ashish A Lahousse Lies L Li Guo G Lind Lars L Lindgren Cecilia C Liu Yongmei Y Lohman Kurt K Lumley Thomas T McArdle Wendy L WL Meibohm Bernd B Morris Andrew P AP Morrison Alanna C AC Musk Bill B North Kari E KE Palmer Lyle J LJ Probst-Hensch Nicole M NM Psaty Bruce M BM Rivadeneira Fernando F Rotter Jerome I JI Schulz Holger H Smith Lewis J LJ Sood Akshay A Starr John M JM Strachan David P DP Teumer Alexander A Uitterlinden André G AG Völzke Henry H Voorman Arend A Wain Louise V LV Wells Martin T MT Wilk Jemma B JB Williams O Dale OD Heckbert Susan R SR Stricker Bruno H BH London Stephanie J SJ Fornage Myriam M Tobin Martin D MD O'Connor George T GT Hall Ian P IP Cassano Patricia A PA

PloS one 20140701 7

<h4>Background</h4>Genome-wide association studies (GWAS) have identified numerous loci influencing cross-sectional lung function, but less is known about genes influencing longitudinal change in lung function.<h4>Methods</h4>We performed GWAS of the rate of change in forced expiratory volume in the first second (FEV1) in 14 longitudinal, population-based cohort studies comprising 27,249 adults of European ancestry using linear mixed effects model and combined cohort-specific results using fixed ...[more]

PMID: 24983941

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Project description:BackgroundObservational studies examining associations between adult height and risk of colorectal, prostate, and lung cancers have generated mixed results. We conducted meta-analyses using data from prospective cohort studies and further carried out Mendelian randomization analyses, using height-associated genetic variants identified in a genome-wide association study (GWAS), to evaluate the association of adult height with these cancers.Methods and findingsA systematic review of prospective studies was conducted using the PubMed, Embase, and Web of Science databases. Using meta-analyses, results obtained from 62 studies were summarized for the association of a 10-cm increase in height with cancer risk. Mendelian randomization analyses were conducted using summary statistics obtained for 423 genetic variants identified from a recent GWAS of adult height and from a cancer genetics consortium study of multiple cancers that included 47,800 cases and 81,353 controls. For a 10-cm increase in height, the summary relative risks derived from the meta-analyses of prospective studies were 1.12 (95% CI 1.10, 1.15), 1.07 (95% CI 1.05, 1.10), and 1.06 (95% CI 1.02, 1.11) for colorectal, prostate, and lung cancers, respectively. Mendelian randomization analyses showed increased risks of colorectal (odds ratio [OR] = 1.58, 95% CI 1.14, 2.18) and lung cancer (OR = 1.10, 95% CI 1.00, 1.22) associated with each 10-cm increase in genetically predicted height. No association was observed for prostate cancer (OR = 1.03, 95% CI 0.92, 1.15). Our meta-analysis was limited to published studies. The sample size for the Mendelian randomization analysis of colorectal cancer was relatively small, thus affecting the precision of the point estimate.ConclusionsOur study provides evidence for a potential causal association of adult height with the risk of colorectal and lung cancers and suggests that certain genetic factors and biological pathways affecting adult height may also affect the risk of these cancers.

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Large-scale genome-wide association studies and meta-analyses of longitudinal change in adult lung function.

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Large-scale genome-wide association studies and meta-analyses of longitudinal change in adult lung function.

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