Linking the gut microbiome to host DNA methylation by a discovery and replication epigenome-wide association study

Ayşe Demirkan; Jenny van Dongen; Casey T Finnicum; Harm-Jan Westra; Soesma Jankipersadsing; Gonneke Willemsen; Richard G Ijzerman; Dorret I Boomsma; Erik A Ehli; Marc Jan Bonder; Jingyuan Fu; Lude Franke; Cisca Wijmenga; Eco J C de Geus; Alexander Kurilshikov; Alexandra Zhernakova

doi:10.1186/s12864-024-11136-x

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Linking the gut microbiome to host DNA methylation by a discovery and replication epigenome-wide association study

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Linking the gut microbiome to host DNA methylation by a discovery and replication epigenome-wide association study

Ayşe Demirkan, Jenny van Dongen, Casey T Finnicum, Harm-Jan Westra, Soesma Jankipersadsing, Gonneke Willemsen, Richard G Ijzerman, Dorret I Boomsma, Erik A Ehli, Marc Jan Bonder, …

BMC genomics, Vol.25, 1224

19/12/2024

DOI: https://doi.org/10.1186/s12864-024-11136-x

PMID: 39702006

Abstract

Adult

CpG Islands - genetics

DNA Methylation

Epigenome

Female

Gastrointestinal Microbiome - genetics

Genome-Wide Association Study

Humans

Male

Middle Aged

RNA, Ribosomal, 16S - genetics

Netherlands

Microbiome influences multiple human systems, but its effects on gene methylation is unknown. We investigated the relations between gene methylation in blood and the abundance of common gut bacteria profiled by 16s rRNA gene sequencing in two population-based Dutch cohorts: LifeLines-Deep (LLD, n = 616, discovery) and the Netherlands Twin Register (NTR, n = 296, replication). In LLD, we also explored microbial pathways using data generated by shotgun metagenomic sequencing (n = 683). Methylation in both cohorts was profiled in blood samples using the Illumina 450K array. Discovery and replication analysis identified two independent CpGs associated with the genus Eggerthella: cg16586104 (P = 3.21 × 10 ) and cg12234533 (P = 4.29 × 10 ). We also show that microbiome can mediate the effect of environmental factors on host gene methylation. In this first association study linking epigenome to microbiome, we found and replicated the associations of two CpGs to the abundance of genus Eggerthella and identified microbiome as a mediator of the exposome. These associations are observational and suggest further investigation in larger and longitudinal set-ups.

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Title: Linking the gut microbiome to host DNA methylation by a discovery and replication epigenome-wide association study
Creators: Ayşe Demirkan - University of Surrey, Institute for Sustainability
Jenny van Dongen - Vrije Universiteit Amsterdam
Casey T Finnicum - Avera Institute of Human Genetics, Avera McKennan Hospital & University Health Center, Sioux Falls, Sioux Falls, SD, USA
Harm-Jan Westra - University of Groningen
Soesma Jankipersadsing - University of Groningen
Gonneke Willemsen - Vrije Universiteit Amsterdam
Richard G Ijzerman - Amsterdam University Medical Centers
Dorret I Boomsma - University of Amsterdam
Erik A Ehli - Avera McKennan Hospital & University Health Center
Marc Jan Bonder - University of Groningen
Jingyuan Fu - University of Groningen
Lude Franke - University of Groningen
Cisca Wijmenga - University of Groningen
Eco J C de Geus - Vrije Universiteit Amsterdam
Alexander Kurilshikov - University of Groningen
Alexandra Zhernakova - University of Groningen
Publication Details: BMC genomics, Vol.25, 1224
Publisher: Springer
Publication Date: 19/12/2024
Date accepted for publication: 06/12/2024
Grant note: AZ is supported by the Netherlands Organization for Scientific Research (NWO)-VIDI grant 016.178.056, Netherlands Heart Foundation CVON grant 2018-27. AK and AZ are supported by the NWO Gravitation grant ExposomeNL 024.004.017. The Lifelines initiative has been made possible by subsidy from the Dutch Ministry of Health, Welfare and Sport, the Dutch Ministry of Economic Affairs, the University Medical Center Groningen (UMCG), Groningen University and the Provinces in the North of the Netherlands (Drenthe, Friesland, Groningen). The Netherlands Twin Register acknowledges funding from the Netherlands Organization for Scientific Research (NWO): (NWO 911–09–032; NWO 480-04-004; 480-15-001/674, NWO 916-130-82), Biobanking and Biomolecular Research Infrastructure (184.033.111), and the BBRMI-NL-financed BIOS Consortium (NWO 184.021.007), NWO Large Scale infrastructures X-Omics (184.034.019), Genotype/phenotype database for behaviour genetic and genetic epidemiological studies (ZonMw Middelgroot 911-09-032); Netherlands Twin Registry Repository: researching the interplay between genome and environment (NWO-Groot 480-15-001/674); the Avera Institute, Sioux Falls (USA), the European Research Council (Genetics of Mental Illness 230374), the European Research Council (Genetics of Mental Illness 230374), and INRA-Pfizer. Pfizer provided support for data collection, but did not have any additional role in the study design, data analysis, decision to publish, or preparation of the manuscript. JF is supported by the ERC Consolidator grant (grant agreement No. 101001678), NWO-VICI grant VI.C.202.022, the AMMODO Science Award 2023 for Biomedical Sciences from Stichting Ammodo, and NWO-KIC project (KICH1.LWV04.21.013).
Identifiers: 99960266502346; WOS:001380779800006
Academic Unit: Institute for Sustainability; School of Biosciences; Surrey Institute for People-Centred AI
Language: English
Resource Type: Journal article
Data Access Statement: The raw sequence data for both MGS and 16S rRNA gene sequencing data sets, and age and gender information per sample are available from the European genome-phenome archive (https://www.ebi.ac.uk/ega/) at accession number EGAS00001001704. Other phenotypic data can be requested from the LifeLines cohort study (https://lifelines.nl/lifelines-research/access-to-lifelines) following the standard protocol for data access. All data access to the Lifelines population cohort must follow the informed consent regulations of the Medical Ethics Review Board of the University Medical Center Groningen, which are clearly described at https://lifelines.nl/upload/file/lifelines+data+access+policy_%5B1%5D.pdf.The pipeline for DNA methylation-array analysis developed by the Biobank-based Integrative Omics Study (BIOS) consortium are available here: https://molepi.github.io/DNAmArray_workflow/ (https://doi.org/10.5281/zenodo.3355292). The HumanMethylation450 BeadChip data from the LLD and NTR are available as part of the Biobank-based Integrative Omics Studies (BIOS) Consortium in the European Genome-phenome Archive (EGA), under the accession code EGAD00010000887, https://ega-archive.org/datasets/EGAD00010000887. The OMICs data and additional phenotype data are available upon request via the BBMRI-NL BIOS consortium (https://www.bbmri.nl/acquisition-use-analyze/bios). All NTR data can be requested by bona fida researchers (https://ntr-data-request.psy.vu.nl/).Summary statistics of microbiome EWAS form LLD on 16s taxa, shotgun metagenomics derived taxa and pathways are deposited on https://doi.org/10.5281/zenodo.10062077. Consent for publication: N/A. No identifying images or other personal or clinical details of participants are presented.

Linking the gut microbiome to host DNA methylation by a discovery and replication epigenome-wide association study

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