Genome-wide association studies identify CHRNA5/3 and HTR4 in the development of airflow obstruction.
RATIONALE: Genome-wide association studies (GWAS) have identified loci influencing lung function, but fewer genes influencing chronic obstructive pulmonary disease (COPD) are known. OBJECTIVES: Perform meta-analyses of GWAS for airflow obstruction, a key pathophysiologic characteristic of COPD assessed by spirometry, in population-based cohorts examining all participants, ever smokers, never smokers, asthma-free participants, and more severe cases. METHODS: Fifteen cohorts were studied for discovery (3,368 affected; 29,507 unaffected), and a population-based family study and a meta-analysis of case-control studies were used for replication and regional follow-up (3,837 cases; 4,479 control subjects). Airflow obstruction was defined as FEV(1) and its ratio to FVC (FEV(1)/FVC) both less than their respective lower limits of normal as determined by published reference equations. MEASUREMENTS AND MAIN RESULTS: The discovery meta-analyses identified one region on chromosome 15q25.1 meeting genome-wide significance in ever smokers that includes AGPHD1, IREB2, and CHRNA5/CHRNA3 genes. The region was also modestly associated among never smokers. Gene expression studies confirmed the presence of CHRNA5/3 in lung, airway smooth muscle, and bronchial epithelial cells. A single-nucleotide polymorphism in HTR4, a gene previously related to FEV(1)/FVC, achieved genome-wide statistical significance in combined meta-analysis. Top single-nucleotide polymorphisms in ADAM19, RARB, PPAP2B, and ADAMTS19 were nominally replicated in the COPD meta-analysis. CONCLUSIONS: These results suggest an important role for the CHRNA5/3 region as a genetic risk factor for airflow obstruction that may be independent of smoking and implicate the HTR4 gene in the etiology of airflow obstruction.
Wilk, JB; Shrine, NRG; Loehr, LR; Zhao, JH; Manichaikul, A; Lopez, LM; Smith, AV; Heckbert, SR; Smolonska, J; Tang, W; Loth, DW; Curjuric, I; Hui, J; Cho, MH; Latourelle, JC; Henry, AP; Aldrich, M; Bakke, P; Beaty, TH; Bentley, AR; Borecki, IB; Brusselle, GG; Burkart, KM; Chen, T-H; Couper, D; Crapo, JD; Davies, G; Dupuis, J; Franceschini, N; Gulsvik, A; Hancock, DB; Harris, TB; Hofman, A; Imboden, M; James, AL; Khaw, K-T; Lahousse, L; Launer, LJ; Litonjua, A; Liu, Y; Lohman, KK; Lomas, DA; Lumley, T; Marciante, KD; McArdle, WL; Meibohm, B; Morrison, AC; Musk, AW; Myers, RH; North, KE; Postma, DS; Psaty, BM; Rich, SS; Rivadeneira, F; Rochat, T; Rotter, JI; Soler Artigas, M; Starr, JM; Uitterlinden, AG; Wareham, NJ; Wijmenga, C; Zanen, P; Province, MA; Silverman, EK; Deary, IJ; Palmer, LJ; Cassano, PA; Gudnason, V; Barr, RG; Loos, RJF; Strachan, DP; London, SJ; Boezen, HM; Probst-Hensch, N; Gharib, SA; Hall, IP; O'Connor, GT; Tobin, MD; Stricker, BH
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