Document Type

Article

Publication Date

2021

DOI

10.1136/thoraxjnl-2020-215624

Publication Title

Thorax

Volume

76

Pages

1219-1226

Abstract

Rationale Genome-wide association studies (GWASs) have identified numerous loci associated with lower pulmonary function. Pulmonary function is strongly related to smoking and has also been associated with asthma and dust endotoxin. At the individual SNP level, genome-wide analyses of pulmonary function have not identified appreciable evidence for gene by environment interactions. Genetic Risk Scores (GRSs) may enhance power to identify gene–environment interactions, but studies are few.

Methods We analysed 2844 individuals of European ancestry with 1000 Genomes imputed GWAS data from a case–control study of adult asthma nested within a US agricultural cohort. Pulmonary function traits were FEV1, FVC and FEV1/FVC. Using data from a recent large meta-analysis of GWAS, we constructed a weighted GRS for each trait by combining the top (p value<5×10−9) genetic variants, after clumping based on distance (±250 kb) and linkage disequilibrium (r2=0.5). We used linear regression, adjusting for relevant covariates, to estimate associations of each trait with its GRS and to assess interactions.

Results Each trait was highly significantly associated with its GRS (all three p values<8.9×10−8). The inverse association of the GRS with FEV1/FVC was stronger for current smokers (pinteraction=0.017) or former smokers (pinteraction=0.064) when compared with never smokers and among asthmatics compared with non-asthmatics (pinteraction=0.053). No significant interactions were observed between any GRS and house dust endotoxin.

Conclusions Evaluation of interactions using GRSs supports a greater impact of increased genetic susceptibility on reduced pulmonary function in the presence of smoking or asthma.

Rights

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial.

© Authors (or their employers) 2021

Data Availability

Article states: Data are available upon reasonable request pending all required approvals.

Original Publication Citation

Sikdar, S., Wyss, A.B., Lee, M.K., Hoang, T.T., Richards, M., Beane Freeman, L.E., Parks, C., Thorne, P.S., Hankinson, J.L., Umbach, D.M., Motsinger-Reif, A., & London, S.J. (2021). Interaction between Genetic Risk Scores for reduced pulmonary function and smoking, asthma and endotoxin. Thorax 76, 1219-1226. https://doi.org/10.1136/thoraxjnl-2020-215624

ORCID

0000-0003-1230-5162 (Sikdar)

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