Limited overlap in significant hits between genome-wide association studies on two airflow obstruction definitions in the same population View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2019-12

AUTHORS

Diana A. van der Plaat, Judith M. Vonk, Lies Lahousse, Kim de Jong, Alen Faiz, Ivana Nedeljkovic, Najaf Amin, Cleo C. van Diemen, Guy G. Brusselle, Yohan Bossé, Corry-Anke Brandsma, Ke Hao, Peter D. Paré, Cornelia M. van Duijn, Dirkje S. Postma, H. Marike Boezen

ABSTRACT

BACKGROUND: Airflow 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. METHODS: GWASes 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). RESULTS: In 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. CONCLUSIONS: The 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. More... »

PAGES

58

Identifiers

URI

http://scigraph.springernature.com/pub.10.1186/s12890-019-0811-0

DOI

http://dx.doi.org/10.1186/s12890-019-0811-0

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1112606542

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/30845926


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