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Open Access 01-12-2019 | Chronic Obstructive Lung Disease | Research article

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

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

Published in: BMC Pulmonary Medicine | Issue 1/2019

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.

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Title: Limited overlap in significant hits between genome-wide association studies on two airflow obstruction definitions in the same population
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
Publication date: 01-12-2019
Publisher: BioMed Central
Keyword: Chronic Obstructive Lung Disease
Published in: BMC Pulmonary Medicine / Issue 1/2019
Electronic ISSN: 1471-2466
DOI: https://doi.org/10.1186/s12890-019-0811-0

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

Abstract

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Methods

Results

Conclusions

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