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PLoS One DOI:10.1371/journal.pone.0100776

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

Publication TypeJournal Article
Year of Publication2014
AuthorsTang, W, Kowgier, M, Loth, DW, Artigas, MSoler, Joubert, BR, Hodge, E, Gharib, SA, Smith, AV, Ruczinski, I, Gudnason, V, Mathias, RA, Harris, TB, Hansel, NN, Launer, LJ, Barnes, KC, Hansen, JG, Albrecht, E, Aldrich, MC, Allerhand, M, R Barr, G, Brusselle, GG, Couper, DJ, Curjuric, I, Davies, G, Deary, IJ, Dupuis, J, Fall, T, Foy, M, Franceschini, N, Gao, W, Gläser, S, Gu, X, Hancock, DB, Heinrich, J, Hofman, A, Imboden, M, Ingelsson, E, James, A, Karrasch, S, Koch, B, Kritchevsky, SB, Kumar, A, Lahousse, L, Li, G, Lind, L, Lindgren, C, Liu, Y, Lohman, K, Lumley, T, McArdle, WL, Meibohm, B, Morris, AP, Morrison, AC, Musk, B, North, KE, Palmer, LJ, Probst-Hensch, NM, Psaty, BM, Rivadeneira, F, Rotter, JI, Schulz, H, Smith, LJ, Sood, A, Starr, JM, Strachan, DP, Teumer, A, Uitterlinden, AG, Völzke, H, Voorman, A, Wain, LV, Wells, MT, Wilk, JB, O Williams, D, Heckbert, SR, Stricker, BH, London, SJ, Fornage, M, Tobin, MD, O'Connor, GT, Hall, IP, Cassano, PA
JournalPLoS One
Volume9
Issue7
Pagese100776
Date Published2014
ISSN1932-6203
KeywordsAdult, Chromosomes, Human, Pair 11, Female, Gene Expression Regulation, Genetic Loci, Genome-Wide Association Study, Humans, Longitudinal Studies, Male, Respiration
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.

URLhttp://dx.plos.org/10.1371/journal.pone.0100776
DOI10.1371/journal.pone.0100776
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/24983941?dopt=Abstract

Alternate JournalPLoS ONE
PubMed ID24983941
PubMed Central IDPMC4077649
Grant ListETM/55 / / Chief Scientist Office / United Kingdom
N01HC55222 / HC / NHLBI NIH HHS / United States
UL1RR025005 / RR / NCRR NIH HHS / United States
CZB/4/505 / / Chief Scientist Office / United Kingdom
N02-HL-6-4278 / HL / NHLBI NIH HHS / United States
N01-HC-25195 / HC / NHLBI NIH HHS / United States
N01-HC-45205 / HC / NHLBI NIH HHS / United States
098017 / / Wellcome Trust / United Kingdom
UL1TR000124 / TR / NCATS NIH HHS / United States
R01-AG028050 / AG / NIA NIH HHS / United States
U01-HG-004446 / HG / NHGRI NIH HHS / United States
N01-HC-05187 / HC / NHLBI NIH HHS / United States
R01HL59367 / HL / NHLBI NIH HHS / United States
N01HC85080 / HC / NHLBI NIH HHS / United States
N01-HC-48047 / HC / NHLBI NIH HHS / United States
HL085251 / HL / NHLBI NIH HHS / United States
HHSN268201100005C / / PHS HHS / United States
HL105756 / HL / NHLBI NIH HHS / United States
G1000861 / / Medical Research Council / United Kingdom
079895 / / Wellcome Trust / United Kingdom
HHSN268201100009C / / PHS HHS / United States
N01-HC-45204 / HC / NHLBI NIH HHS / United States
/ / Biotechnology and Biological Sciences Research Council / United Kingdom
1R01AG032098-01A1 / AG / NIA NIH HHS / United States
N01-HC-95095 / HC / NHLBI NIH HHS / United States
HHSN268200625226C / / PHS HHS / United States
HL087652 / HL / NHLBI NIH HHS / United States
UL1 TR000124 / TR / NCATS NIH HHS / United States
T32 DK007158 / DK / NIDDK NIH HHS / United States
MR/K026992/1 / / Medical Research Council / United Kingdom
R01-HL-084099 / HL / NHLBI NIH HHS / United States
HHSN268201100010C / / PHS HHS / United States
HHSN268200960009C / / PHS HHS / United States
N01-HC-48050 / HC / NHLBI NIH HHS / United States
U01HG004402 / HG / NHGRI NIH HHS / United States
N01HC85081 / HC / NHLBI NIH HHS / United States
HHSN268200782096C. / / PHS HHS / United States
/ / Intramural NIH HHS / United States
N01HC85079 / HC / NHLBI NIH HHS / United States
N01-HC-45134 / HC / NHLBI NIH HHS / United States
HHSN268201100008C / / PHS HHS / United States
HHSN268201100012C / / PHS HHS / United States
R01HL087641 / HL / NHLBI NIH HHS / United States
WT 084703MA / / Wellcome Trust / United Kingdom
U01-HG-004424 / HG / NHGRI NIH HHS / United States
N01-HC-48049 / HC / NHLBI NIH HHS / United States
090532 / / Wellcome Trust / United Kingdom
N01HC85086 / HC / NHLBI NIH HHS / United States
N01AG62106, / AG / NIA NIH HHS / United States
R01-NR012459, / NR / NINR NIH HHS / United States
N01HC85082 / HC / NHLBI NIH HHS / United States
HHSN268201100007C / / PHS HHS / United States
N01AG62101, / AG / NIA NIH HHS / United States
G0902313 / / Medical Research Council / United Kingdom
WT090532 / / Wellcome Trust / United Kingdom
U01-HG-004729 / HG / NHGRI NIH HHS / United States
Z01 ES43012 / ES / NIEHS NIH HHS / United States
HHSN268200800007C / / PHS HHS / United States
N01-AG-12100 / AG / NIA NIH HHS / United States
HHSN268201100011C / / PHS HHS / United States
DK063491 / DK / NIDDK NIH HHS / United States
G0700704 / / Medical Research Council / United Kingdom
WT098017 / / Wellcome Trust / United Kingdom
/ / Chief Scientist Office / United Kingdom
HHSN268201200036C / / PHS HHS / United States
068545/Z/02 / / Wellcome Trust / United Kingdom
HL080295 / HL / NHLBI NIH HHS / United States
N01HC85083 / HC / NHLBI NIH HHS / United States
BB/F019394/1 / / Biotechnology and Biological Sciences Research Council / United Kingdom
N01-HC-48048 / HC / NHLBI NIH HHS / United States
HHSN268201100006C / / PHS HHS / United States
086596/Z/08/Z / / Wellcome Trust / United Kingdom
HL103612 / HL / NHLBI NIH HHS / United States
WT064890 / / Wellcome Trust / United Kingdom
076113/B/04/Z / / Wellcome Trust / United Kingdom
AG023629 / AG / NIA NIH HHS / United States
N01AG2103, / AG / NIA NIH HHS / United States
G0000934 / / Medical Research Council / United Kingdom
RC1AG035835. / AG / NIA NIH HHS / United States
U01 DK062418 / DK / NIDDK NIH HHS / United States
R01HL086694 / HL / NHLBI NIH HHS / United States