biostudies-literatureTang WIntramural NIH HHSNCATS NIH HHSNIA NIH HHSNCRR NIH HHSNIEHS NIH HHSNHLBI NIH HHSSwiss National Science FoundationNIDDK NIH HHSMedical Research CouncilNINR NIH HHSNHGRI NIH HHSChief Scientist OfficeWellcome TrustPHS HHSBiotechnology and Biological Sciences Research Councile100776https://www.ebi.ac.uk/biostudies/studies/S-EPMC4077649biostudies-literatureUnknown9(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 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.<h4>Results</h4>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.<h4>Conclusions</h4>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.PloS oneLarge-scale genome-wide association studies and meta-analyses of longitudinal change in adult lung function.PMC4077649U01 HG004424079895076113/B/04/ZWT 084703MAHL087652HHSN268201100009IR01 AG023629N01AG2103,U01-HG-004424UL1 RR025005HHSN268201100009CN01HC25195N01HC05187UL1 TR000124G1000861068545/Z/02N01-HC-95095MR/K026992/1R01 NR012459HHSN268200800007CZ01 ES043012Z01 ES43012N01AG62101,P30 DK063491HHSN268200960009CU01 HG004402N01HC95095U01 HL080295ETM/55HHSN268200782096CN02-HL-6-4278AG023629RC1 AG035835G0902313R01-AG028050R01HL086694R01 HL087652UL1TR000124R01 HL077612HL080295HHSN268200625226CHL103612HL105756N01-HC-45134R01 HL080295G0000934R01 HL103612134276R01 HL084099R01 HL105756R01 HL087641098017N01-HC-05187N01-HC-25195R01 AG032098R56 AG023629R01-HL-084099090532R01 HL059367N01HC45204HHSN268201100005CN01HC45205G0700704R01 HL085251HHSN268201100005IR01HL087641HHSN268201100005GBB/F019394/1N01HC480501R01AG032098-01A1N01AG12100CZB/4/505HHSN268201100006CR01HL59367WT064890N01-AG-12100U01 DK062418HHSN268200782096C.T32 DK007158N01HC85079DK063491RC1AG035835.N01HC48049HHSN268201100010CN01HC48048R01 HL086694N01HC48047068545HL085251N01 AG062101U01 HG004446HHSN268201100011IR01 AG028050N01HC85081N01HC85082086596/Z/08/ZN01HC85080HHSN268201200036CN01HC85086HHSN268201100007CN01HC85083U01-HG-004446N01AG62106,N01-HC-48050HHSN268201100011CU01 HG004729HHSN268201100007IUL1RR025005N01-HC-45204U01-HG-004729N01HC55222N01-HC-45205N01-HC-48049N01-HC-48048WT098017HHSN268201100008CN01-HC-48047U01HG004402R01-NR012459,N01 AG062106WT090532HHSN268201100008IHHSN268201100012CN01 HC045134U01 HG004738Brusselle GGAllerhand MLindgren CPsaty BMDupuis JRotter JIVolzke HUitterlinden AGWain LVHansel NNJames AKarrasch SO'Connor GTGudnason VGlaser SMorrison ACKoch BAldrich MCSoler Artigas MCurjuric IJoubert BRDeary IJSmith LJSchulz HWilliams ODStricker BHLi GHall IPKritchevsky SBPalmer LJImboden MLoth DWFranceschini NGharib SAWells MTCouper DJHarris TBDavies GGao WMcArdle WLFornage MSood ATobin MDKowgier MLahousse LLumley TIngelsson EMeibohm BMusk BWilk JBBarr RGHansen JGCassano PAAlbrecht ELiu YLohman KFoy MLind LVoorman AHofman ARuczinski IProbst-Hensch NMSmith AVHancock DBTang WMorris APGu XHeinrich JStrachan DPLondon SJRivadeneira FHeckbert SRMathias RAFall TStarr JMLauner LJBarnes KCTeumer AHodge EKumar ANorth KEfalseLarge-scale genome-wide association studies and meta-analyses of longitudinal change in adult lung function.<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 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.<h4>Results</h4>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.<h4>Conclusions</h4>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.2014-01-01T00:00:00Z20142024-11-09T07:19:44.939Z2019-03-26T23:26:22ZS-EPMC40776492498394110.1371/journal.pone.0100776