Journal
AMERICAN JOURNAL OF HUMAN GENETICS
Volume 106, Issue 3, Pages 315-326Publisher
CELL PRESS
DOI: 10.1016/j.ajhg.2020.01.015
Keywords
-
Categories
Funding
- Integrative Epidemiology Unit from the UK Medical Research Council
- University of Bristol [MC_UU_00011/1, MC_UU_00011/3, MC_UU_00011/4, MC_UU_00011/5, MC_UU_00011/7]
- CRUK [C18281/A19169]
- ESRC [ES/N000498/1]
- Wellcome Trust PhD studentships [203746, 215193/Z18/Z]
- University of Leicester [WT204801/Z/16/Z]
- BHF Accelorator Award [AA/18/3/34220]
- Wellcome Trust Investigator Award [WT202849/Z/16/Z]
- NIHR Biomedical Research Centre at the University Hospitals Bristol NHS Foundation Trust
- NIHR Leicester Biomedical Research Centre
- BBSRC [BB/I025263/1] Funding Source: UKRI
- ESRC [ES/N000498/1] Funding Source: UKRI
- MRC [MC_UU_00011/7, MC_PC_12028, MC_UU_00011/4, MC_UU_00011/3, MC_UU_12013/2, MR/S003886/1, MC_UU_00011/1, MC_PC_19009, MC_UU_00011/5] Funding Source: UKRI
Ask authors/readers for more resources
Whether smoking-associated DNA methylation has a causal effect on lung function has not been thoroughly evaluated. We first investigated the causal effects of 474 smoking-associated CpGs on forced expiratory volume in 1 s (FEV1) in UK Biobank (n = 321,047) by using two-sample Mendelian randomization (MR) and then replicated this investigation in the SpiroMeta Consortium (n = 79,055). Second, we used two-step MR to investigate whether DNA methylation mediates the effect of smoking on FEV1. Lastly, we evaluated the presence of horizontal pleiotropy and assessed whether there is any evidence for shared causal genetic variants between lung function, DNA methylation, and gene expression by using a multiple-trait colocalization (moloc) framework. We found evidence of a possible causal effect for DNA methylation on FEV1 at 18 CpGs (p < 1.2 x 10(-4)). Replication analysis supported a causal effect at three CpGs (cg21201401 [LIME1 and ZGPAT], cg19758448 [PGAP3], and cg12616487 [EML3 and AHNAK] [p < 0.0028]). DNA methylation did not clearly mediate the effect of smoking on FEV1, although DNA methylation at some sites might influence lung function via effects on smoking. By using moloc, we found evidence of shared causal variants between lung function, gene expression, and DNA methylation. These findings highlight potential therapeutic targets for improving lung function and possibly smoking cessation, although larger, tissue-specific datasets are required to confirm these results.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available