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Genome-wide association studies identify CHRNA5/3 and HTR4 in the development of airflow obstruction.

ABSTRACT: 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.

SUBMITTER: Wilk JB

PROVIDER: S-EPMC3480517 | biostudies-literature | 2012 Oct

REPOSITORIES: biostudies-literature

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Genome-wide association studies identify CHRNA5/3 and HTR4 in the development of airflow obstruction.

Wilk Jemma B JB Shrine Nick R G NR Loehr Laura R LR Zhao Jing Hua JH Manichaikul Ani A Lopez Lorna M LM Smith Albert Vernon AV Heckbert Susan R SR Smolonska Joanna J Tang Wenbo W Loth Daan W DW Curjuric Ivan I Hui Jennie J Cho Michael H MH Latourelle Jeanne C JC Henry Amanda P AP Aldrich Melinda M Bakke Per P Beaty Terri H TH Bentley Amy R AR Borecki Ingrid B IB Brusselle Guy G GG Burkart Kristin M KM Chen Ting-hsu TH Couper David D Crapo James D JD Davies Gail G Dupuis Josée J Franceschini Nora N Gulsvik Amund A Hancock Dana B DB Harris Tamara B TB Hofman Albert A Imboden Medea M James Alan L AL Khaw Kay-Tee KT Lahousse Lies L Launer Lenore J LJ Litonjua Augusto A Liu Yongmei Y Lohman Kurt K KK Lomas David A DA Lumley Thomas T Marciante Kristin D KD McArdle Wendy L WL Meibohm Bernd B Morrison Alanna C AC Musk Arthur W AW Myers Richard H RH North Kari E KE Postma Dirkje S DS Psaty Bruce M BM Rich Stephen S SS Rivadeneira Fernando F Rochat Thierry T Rotter Jerome I JI Soler Artigas María M Starr John M JM Uitterlinden André G AG Wareham Nicholas J NJ Wijmenga Cisca C Zanen Pieter P Province Michael A MA Silverman Edwin K EK Deary Ian J IJ Palmer Lyle J LJ Cassano Patricia A PA Gudnason Vilmundur V Barr R Graham RG Loos Ruth J F RJ Strachan David P DP London Stephanie J SJ Boezen H Marike HM Probst-Hensch Nicole N Gharib Sina A SA Hall Ian P IP O'Connor George T GT Tobin Martin D MD Stricker Bruno H BH

American journal of respiratory and critical care medicine 20120726 7

<h4>Rationale</h4>Genome-wide association studies (GWAS) have identified loci influencing lung function, but fewer genes influencing chronic obstructive pulmonary disease (COPD) are known.<h4>Objectives</h4>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.<h4>Methods</h4>Fifteen cohorts wer ...[more]

PMID: 22837378

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Project description:BackgroundAirflow obstruction is a hallmark of chronic obstructive pulmonary disease (COPD), and is defined as either the ratio between forced expiratory volume in one second and forced vital capacity (FEV1/FVC) < 70% or < lower limit of normal (LLN). This study aimed to assess the overlap between genome-wide association studies (GWAS) on airflow obstruction using these two definitions in the same population stratified by smoking.MethodsGWASes were performed in the LifeLines Cohort Study for both airflow obstruction definitions in never-smokers (NS = 5071) and ever-smokers (ES = 4855). The FEV1/FVC < 70% models were adjusted for sex, age, and height; FEV1/FVC < LLN models were not adjusted. Ever-smokers models were additionally adjusted for pack-years and current-smoking. The overlap in significantly associated SNPs between the two definitions and never/ever-smokers was assessed using several p-value thresholds. To quantify the agreement, the Pearson correlation coefficient was calculated between the p-values and ORs. Replication was performed in the Vlagtwedde-Vlaardingen study (NS = 432, ES = 823). The overlapping SNPs with p < 10- 4 were validated in the Vlagtwedde-Vlaardingen and Rotterdam Study cohorts (NS = 1966, ES = 3134) and analysed for expression quantitative trait loci (eQTL) in lung tissue (n = 1087).ResultsIn the LifeLines cohort, 96% and 93% of the never- and ever-smokers were classified concordantly based on the two definitions. 26 and 29% of the investigated SNPs were overlapping at p < 0.05 in never- and ever-smokers, respectively. At p < 10- 4 the overlap was 4% and 6% respectively, which could be change findings as shown by simulation studies. The effect estimates of the SNPs of the two definitions correlated strongly, but the p-values showed more variation and correlated only moderately. Similar observations were made in the Vlagtwedde-Vlaardingen study. Two overlapping SNPs in never-smokers (NFYC and FABP7) had the same direction of effect in the validation cohorts and the NFYC SNP was an eQTL for NFYC-AS1. NFYC is a transcription factor that binds to several known COPD genes, and FABP7 may be involved in abnormal pulmonary development.ConclusionsThe definition of airflow obstruction and the population under study may be important determinants of which SNPs are associated with airflow obstruction. The genes FABP7 and NFYC(-AS1) could play a role in airflow obstruction in never-smokers specifically.

Project description:Plants synthesize specialized metabolites to facilitate environmental and ecological interactions. During evolution, plants diversified in their potential to synthesize these metabolites. Quantitative differences in metabolite levels of natural Arabidopsis (Arabidopsis thaliana) accessions can be employed to unravel the genetic basis for metabolic traits using genome-wide association studies (GWAS). Here, we performed metabolic GWAS on seeds of a panel of 315 A. thaliana natural accessions, including the reference genotypes C24 and Col-0, for polar and semi-polar seed metabolites using untargeted ultra-performance liquid chromatography-mass spectrometry. As a complementary approach, we performed quantitative trait locus (QTL) mapping of near-isogenic introgression lines between C24 and Col-0 for specific seed specialized metabolites. Besides common QTL between seeds and leaves, GWAS revealed seed-specific QTL for specialized metabolites, indicating differences in the genetic architecture of seeds and leaves. In seeds, aliphatic methylsulfinylalkyl and methylthioalkyl glucosinolates associated with the ALKENYL HYDROXYALKYL PRODUCING loci (GS-ALK and GS-OHP) on chromosome 4 containing alkenyl hydroxyalkyl producing 2 (AOP2) and 3 (AOP3) or with the GS-ELONG locus on chromosome 5 containing methylthioalkyl malate synthase (MAM1) and MAM3. We detected two unknown sulfur-containing compounds that were also mapped to these loci. In GWAS, some of the annotated flavonoids (kaempferol 3-O-rhamnoside-7-O-rhamnoside, quercetin 3-O-rhamnoside-7-O-rhamnoside) were mapped to transparent testa 7 (AT5G07990), encoding a cytochrome P450 75B1 monooxygenase. Three additional mass signals corresponding to quercetin-containing flavonols were mapped to UGT78D2 (AT5G17050). The association of the loci and associating metabolic features were functionally verified in knockdown mutant lines. By performing GWAS and QTL mapping, we were able to leverage variation of natural populations and parental lines to study seed specialized metabolism. The GWAS data set generated here is a high-quality resource that can be investigated in further studies.

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Genome-wide association studies identify CHRNA5/3 and HTR4 in the development of airflow obstruction.

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Genome-wide association studies identify CHRNA5/3 and HTR4 in the development of airflow obstruction.

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