The University of Southampton
University of Southampton Institutional Repository
Warning ePrints Soton is experiencing an issue with some file downloads not being available. We are working hard to fix this. Please bear with us.

Role of DNA methylation in the association of lung function with body mass index: a two-step epigenetic Mendelian randomisation study

Role of DNA methylation in the association of lung function with body mass index: a two-step epigenetic Mendelian randomisation study
Role of DNA methylation in the association of lung function with body mass index: a two-step epigenetic Mendelian randomisation study

BACKGROUND: Low lung function has been associated with increased body mass index (BMI). The aim of this study was to investigate whether the effect of BMI on lung function is mediated by DNA methylation.

METHODS: We used individual data from 285,495 participants in four population-based cohorts: the European Community Respiratory Health Survey, the Northern Finland Birth Cohort 1966, the Swiss Study on Air Pollution and Lung Disease in Adults, and the UK Biobank. We carried out Mendelian randomisation (MR) analyses in two steps using a two-sample approach with SNPs as instrumental variables (IVs) in each step. In step 1 MR, we estimated the causal effect of BMI on peripheral blood DNA methylation (measured at genome-wide level) using 95 BMI-associated SNPs as IVs. In step 2 MR, we estimated the causal effect of DNA methylation on FEV 1, FVC, and FEV 1/FVC using two SNPs acting as methQTLs occurring close (in cis) to CpGs identified in the first step. These analyses were conducted after exclusion of weak IVs (F statistic < 10) and MR estimates were derived using the Wald ratio, with standard error from the delta method. Individuals whose data were used in step 1 were not included in step 2.

RESULTS: In step 1, we found that BMI might have a small causal effect on DNA methylation levels (less than 1% change in methylation per 1 kg/m2 increase in BMI) at two CpGs (cg09046979 and cg12580248). In step 2, we found no evidence of a causal effect of DNA methylation at cg09046979 on lung function. We could not estimate the causal effect of DNA methylation at cg12580248 on lung function as we could not find publicly available data on the association of this CpG with SNPs.

CONCLUSIONS: To our knowledge, this is the first paper to report the use of a two-step MR approach to assess the role of DNA methylation in mediating the effect of a non-genetic factor on lung function. Our findings do not support a mediating effect of DNA methylation in the association of lung function with BMI.

Body mass index, DNA methylation, Effect mediation, Lung function, Mendelian randomisation
1471-2466
171
Amaral, André F. S.
dbecedaa-04b7-43da-9bcb-c4e1f3e471fc
Imboden, Medea
7ac4495d-e803-4e18-b6ba-318da568f776
Wielscher, Matthias
7ab47d0b-aa3a-43a3-8086-c6b980e56746
Rezwan, Faisal I.
203f8f38-1f5d-485b-ab11-c546b4276338
Minelli, Cosetta
e9c228b2-b94c-4763-bb62-5acb94a7a50b
Garcia-aymerich, Judith
db1f2bf3-b293-45e6-aaa7-2f7a6fe9b593
Peralta, Gabriela P.
4a1dc06f-722b-468f-aa31-4e5cca3ae8e4
Auvinen, Juha
edadee31-2f78-442d-903f-a3e5b83ed61f
Jeong, Ayoung
d742adca-f0fd-4da7-89ba-a01b5e879664
Schaffner, Emmanuel
293d2f9d-6359-4e3f-93ce-b8c052c888a3
Beckmeyer-borowko, Anna
c5d69b6f-f137-402c-b716-70865225724f
Holloway, John W.
4bbd77e6-c095-445d-a36b-a50a72f6fe1a
Jarvelin, Marjo-riitta
54bf0cc8-8f32-47db-b22d-6e694f1c1b26
Probst-hensch, Nicole M.
8884fbd3-d87a-4399-a433-db615089ef68
Jarvis, Deborah L.
9e8ece92-3265-42e4-9240-2beccacb00cd
Amaral, André F. S.
dbecedaa-04b7-43da-9bcb-c4e1f3e471fc
Imboden, Medea
7ac4495d-e803-4e18-b6ba-318da568f776
Wielscher, Matthias
7ab47d0b-aa3a-43a3-8086-c6b980e56746
Rezwan, Faisal I.
203f8f38-1f5d-485b-ab11-c546b4276338
Minelli, Cosetta
e9c228b2-b94c-4763-bb62-5acb94a7a50b
Garcia-aymerich, Judith
db1f2bf3-b293-45e6-aaa7-2f7a6fe9b593
Peralta, Gabriela P.
4a1dc06f-722b-468f-aa31-4e5cca3ae8e4
Auvinen, Juha
edadee31-2f78-442d-903f-a3e5b83ed61f
Jeong, Ayoung
d742adca-f0fd-4da7-89ba-a01b5e879664
Schaffner, Emmanuel
293d2f9d-6359-4e3f-93ce-b8c052c888a3
Beckmeyer-borowko, Anna
c5d69b6f-f137-402c-b716-70865225724f
Holloway, John W.
4bbd77e6-c095-445d-a36b-a50a72f6fe1a
Jarvelin, Marjo-riitta
54bf0cc8-8f32-47db-b22d-6e694f1c1b26
Probst-hensch, Nicole M.
8884fbd3-d87a-4399-a433-db615089ef68
Jarvis, Deborah L.
9e8ece92-3265-42e4-9240-2beccacb00cd

Amaral, André F. S., Imboden, Medea, Wielscher, Matthias, Rezwan, Faisal I., Minelli, Cosetta, Garcia-aymerich, Judith, Peralta, Gabriela P., Auvinen, Juha, Jeong, Ayoung, Schaffner, Emmanuel, Beckmeyer-borowko, Anna, Holloway, John W., Jarvelin, Marjo-riitta, Probst-hensch, Nicole M. and Jarvis, Deborah L. (2020) Role of DNA methylation in the association of lung function with body mass index: a two-step epigenetic Mendelian randomisation study. BMC Pulmonary Medicine, 20 (1), 171, [171]. (doi:10.1186/s12890-020-01212-9).

Record type: Article

Abstract

BACKGROUND: Low lung function has been associated with increased body mass index (BMI). The aim of this study was to investigate whether the effect of BMI on lung function is mediated by DNA methylation.

METHODS: We used individual data from 285,495 participants in four population-based cohorts: the European Community Respiratory Health Survey, the Northern Finland Birth Cohort 1966, the Swiss Study on Air Pollution and Lung Disease in Adults, and the UK Biobank. We carried out Mendelian randomisation (MR) analyses in two steps using a two-sample approach with SNPs as instrumental variables (IVs) in each step. In step 1 MR, we estimated the causal effect of BMI on peripheral blood DNA methylation (measured at genome-wide level) using 95 BMI-associated SNPs as IVs. In step 2 MR, we estimated the causal effect of DNA methylation on FEV 1, FVC, and FEV 1/FVC using two SNPs acting as methQTLs occurring close (in cis) to CpGs identified in the first step. These analyses were conducted after exclusion of weak IVs (F statistic < 10) and MR estimates were derived using the Wald ratio, with standard error from the delta method. Individuals whose data were used in step 1 were not included in step 2.

RESULTS: In step 1, we found that BMI might have a small causal effect on DNA methylation levels (less than 1% change in methylation per 1 kg/m2 increase in BMI) at two CpGs (cg09046979 and cg12580248). In step 2, we found no evidence of a causal effect of DNA methylation at cg09046979 on lung function. We could not estimate the causal effect of DNA methylation at cg12580248 on lung function as we could not find publicly available data on the association of this CpG with SNPs.

CONCLUSIONS: To our knowledge, this is the first paper to report the use of a two-step MR approach to assess the role of DNA methylation in mediating the effect of a non-genetic factor on lung function. Our findings do not support a mediating effect of DNA methylation in the association of lung function with BMI.

Text
Amaral-BMCPM-2020 - Version of Record
Available under License Creative Commons Attribution.
Download (893kB)

More information

Accepted/In Press date: 9 June 2020
Published date: 16 June 2020
Keywords: Body mass index, DNA methylation, Effect mediation, Lung function, Mendelian randomisation

Identifiers

Local EPrints ID: 441810
URI: http://eprints.soton.ac.uk/id/eprint/441810
ISSN: 1471-2466
PURE UUID: 2a1f746e-a5d4-4f8b-a852-f9a2cc5ae7d8
ORCID for Faisal I. Rezwan: ORCID iD orcid.org/0000-0001-9921-222X
ORCID for John W. Holloway: ORCID iD orcid.org/0000-0001-9998-0464

Catalogue record

Date deposited: 29 Jun 2020 16:30
Last modified: 17 Jul 2021 01:48

Export record

Altmetrics

Contributors

Author: André F. S. Amaral
Author: Medea Imboden
Author: Matthias Wielscher
Author: Faisal I. Rezwan ORCID iD
Author: Cosetta Minelli
Author: Judith Garcia-aymerich
Author: Gabriela P. Peralta
Author: Juha Auvinen
Author: Ayoung Jeong
Author: Emmanuel Schaffner
Author: Anna Beckmeyer-borowko
Author: Marjo-riitta Jarvelin
Author: Nicole M. Probst-hensch
Author: Deborah L. Jarvis

Download statistics

Downloads from ePrints over the past year. Other digital versions may also be available to download e.g. from the publisher's website.

View more statistics

Atom RSS 1.0 RSS 2.0

Contact ePrints Soton: eprints@soton.ac.uk

ePrints Soton supports OAI 2.0 with a base URL of http://eprints.soton.ac.uk/cgi/oai2

This repository has been built using EPrints software, developed at the University of Southampton, but available to everyone to use.

We use cookies to ensure that we give you the best experience on our website. If you continue without changing your settings, we will assume that you are happy to receive cookies on the University of Southampton website.

×