Genome-Wide Association Studies Identify CHRNA5/3 and HTR4 in the Development of Airflow Obstruction

Division of Aging, Brigham and Women's Hospital and Harvard Medical School, 1620 Tremont Street, 3rd Floor, Boston, MA 02120. .
American Journal of Respiratory and Critical Care Medicine (Impact Factor: 13). 07/2012; 186(7):622-32. DOI: 10.1164/rccm.201202-0366OC
Source: PubMed


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 FEV1 and its ratio to FVC (FEV1/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 FEV1/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.

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Available from: Jerome I Rotter
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    • "To study the genetic component of COPD, genome-wide association (GWA) studies have attempted to identify genetic determinants of human lung function in healthy subjects, using spirometry data on Forced Expiratory Volume in one second (FEV)1 and its ratio to Forced Vital Capacity (FVC) (FEV1/FVC). To date, a total of 26 genetic loci for human lung function have been identified, some of which also seem to be associated with COPD susceptibility, such as the loci at TNS1, RARB, FAM13A, GSTCD, HHIP, ADAM19, HTR4, AGER, GPR126, C10orf11 and THSD4 [7], [8], [9], [10], [11]. "
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    • "Several genome-wide association studies have linked chromosome 15q24-q25.1, a region containing the genes encoding the α3, α5, and β4 subunits of neuronal nicotinic receptors, with nicotine dependence and smoking-related illnesses such as lung cancer, airflow obstruction, and chronic obstructive pulmonary disease [1]–[6]. In candidate gene association studies, variants in the CHRNA5-A3-B4 gene cluster have been associated with nicotine dependence [7]–[14], smoking behaviors [15], [16], level of response to alcohol [17], age of initiation of drinking [15] and cocaine dependence [11], [18]. "
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    ABSTRACT: Variants within the gene cluster encoding α3, α5, and β4 nicotinic receptor subunits are major risk factors for substance dependence. The strongest impact on risk is associated with variation in the CHRNA5 gene, where at least two mechanisms are at work: amino acid variation and altered mRNA expression levels. The risk allele of the non-synonymous variant (rs16969968; D398N) primarily occurs on the haplotype containing the low mRNA expression allele. In populations of European ancestry, there are approximately 50 highly correlated variants in the CHRNA5-CHRNA3-CHRNB4 gene cluster and the adjacent PSMA4 gene region that are associated with CHRNA5 mRNA levels. It is not clear which of these variants contribute to the changes in CHRNA5 transcript level. Because populations of African ancestry have reduced linkage disequilibrium among variants spanning this gene cluster, eQTL mapping in subjects of African ancestry could potentially aid in defining the functional variants that affect CHRNA5 mRNA levels. We performed quantitative allele specific gene expression using frontal cortices derived from 49 subjects of African ancestry and 111 subjects of European ancestry. This method measures allele-specific transcript levels in the same individual, which eliminates other biological variation that occurs when comparing expression levels between different samples. This analysis confirmed that substance dependence associated variants have a direct cis-regulatory effect on CHRNA5 transcript levels in human frontal cortices of African and European ancestry and identified 10 highly correlated variants, located in a 9 kb region, that are potential functional variants modifying CHRNA5 mRNA expression levels.
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    • "A study that investigated single nucleotide polymorphisms (SNPs) of the fibrinogen beta chain-coding gene failed to demonstrate an association between SNPs or related phenotypes and the risk of COPD 27. In addition, a genome-wide study with COPD patients reported that SNPs of fibrinogen-related genes are not associated with the development of COPD 28-34. Therefore, elevated levels of fibrinogen in the subjects with impaired pulmonary function are likely a reflection of disease status rather than a causal factor. "
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