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Paternal body mass index and offspring DNA methylation: findings from the PACE consortium
Rossella Alfano
The Pregnancy and Childhood Epigenetics (PACE) consortium
Deborah A Lawlor
Thorkild IA Sorensen
Janine F Felix
Caroline L Relton
Gemma C Sharp
Stephanie J London
Novel Coronavirus
Acceso Abierto
Background: Accumulating evidence links paternal adiposity in the peri-conceptional period to offspring health outcomes. DNA methylation has been proposed as a mediating mechanism, but very few studies have explored this possibility in humans. Methods and findings: In the Pregnancy And Childhood Epigenetics (PACE) consortium, we conducted a meta-analysis of co-ordinated epigenome-wide association studies (EWAS) of paternal prenatal Body Mass Index (BMI) (with and without adjustment for maternal BMI) in relation to DNA methylation in offspring blood at birth (13 datasets; total n= 4,894) and in childhood (six datasets; total n = 1,982). We found little evidence of association at either time point: for all CpGs, the False Discovery Rate-adjusted P-values were >0.05. In sex-stratified analyses, we found just four CpGs where there was robust evidence of association in female offspring. To compare our findings to those of other studies, we conducted a systematic review, which identified seven studies, including five candidate gene studies showing associations between paternal BMI/obesity and offspring or sperm DNA methylation at imprinted regions. However, in our own study, we found very little evidence of enrichment for imprinted genes. Conclusion: Our findings do not support the hypothesis that paternal BMI around the time of pregnancy is associated with offspring blood DNA methylation, even at imprinted regions. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement Cohort-specific funding statements ALSPAC: GCS, DAL, GDS, PY and CLR are members of the MRC Integrative Epidemiology Unit, which receives funds from the University of Bristol and United Kingdom Medical Research Council [MC_UU_00011/5 and MC_UU_00011/6]. GCS’s contribution to this work is supported by the Medical Research Council [New Investigator Research Grant, MR/S009310/1] and the European Joint Programming Initiative “A Healthy Diet for a Healthy Life” (JPI HDHL, NutriPROGRAM project, UK MRC MR/S036520/1]. DAL’s contribution to this work is supported by grants from the United States National Institutes of Health [R01 DK1034] and the European Union’s Seventh Framework Programme [FP/2007-2013) / ERC Grant Agreement (Grant number 66945; DevelopObese)]. DAL is a National Institute of Health Research Senior Investigator [NF-SI-0611-10196]. The United Kingdom Medical Research Council and Wellcome (Grant ref: 102215/2/13/2) and the University of Bristol provide core support for ALSPAC. The Accessible Resource for Integrated Epigenomics Studies (ARIES) which generated large scale methylation data was funded by the United Kingdom Biotechnology and Biological Sciences Research Council (BB/I025751/1 and BB/I025263/1). Additional epigenetic profiling on the ALSPAC cohort was supported by the United Kingdom Medical Research Council Integrative Epidemiology Unit and the University of Bristol (MC_UU_12013_1, MC_UU_12013_2, MC_UU_12013_5 and MC_UU_12013_8), the Wellcome Trust (WT088806) and the United States National Institute of Diabetes and Digestive and Kidney Diseases (R01 DK10324). This publication is the work of the authors and Gemma Sharp will serve as guarantors for the contents of this paper. The views expressed in this paper are those of the authors and not necessarily any funders. The funders had no influence on the content of the paper. Born in Bradford (BIB): BiB receives core funding from the Wellcome Trust (WT101597MA), the British Heart Foundation (CS/16/4/32482), a joint grant from the UK Medical Research Council (MRC) and UK Economic and Social Science Research Council (ESRC) (MR/N024397/1) and the National Institute for Health Research (NIHR) under its Collaboration for Applied Health Research and Care (CLAHRC) for Yorkshire and Humber. The research presented in this paper, including obtaining genome-wide and epigenome-wide DNAm data is supported by the US National Institute of Health (R01 DK10324) and European Research Council under the European Union’s Seventh Framework Programme (FP7/2007-2013) / ERC grant agreement no 669545. DAL and GCS work in a unit that receives support from the University of Bristol and UK MRC (MC_UU_00011/6) and DAL is an NIHR senior investigator (NF-SI-330 0611-10196). CHAMACOS: This project was supported by grants from the National Institute of Environmental Health Science (NIEHS) [P01 ESO09605, 5UG30D023356, R01ES021369, R01ES023067, R24ES028529, F31ES027751]; Environmental Protection Agency [RD82670901, RD83451301], and the JPB Foundation. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of NIEHS, EPA, or JPB Foundation. Generation R: The general design of the Generation R Study is made possible by financial support from the Erasmus Medical Center, Rotterdam, the Erasmus University Rotterdam, the Netherlands Organization for Health Research and Development and the Ministry of Health, Welfare and Sport. The EWAS data was funded by a grant to VWJ from the Netherlands Genomics Initiative (NGI)/Netherlands Organisation for Scientific Research (NWO) Netherlands Consortium for Healthy Aging (NCHA; project nr. 050-060-810), by funds from the Genetic Laboratory of the Department of Internal Medicine, Erasmus MC, and by a grant from the National Institute of Child and Human Development (R01HD068437). V.W.J. received a grant from the Netherlands Organization for Health Research and Development (VIDI 016.136.361) and a Consolidator Grant from the European Research Council (ERC-2014-CoG-648916). This project received funding from the European Union’s Horizon 2020 research and innovation programme (733206, LIFECYCLE; 633595 DynaHEALTH; 848158, EarlyCause; 874739, LongITools) and from the European Joint Programming Initiative “A Healthy Diet for a Healthy Life” (JPI HDHL, ZonMw the Netherlands, NutriPROGRAM project, no.529051022 and Precise project no. 529051023). GOYA: Genotyping for the GOYA Study was funded by the Wellcome Trust (Grant ref: 084762MA). Generation of DNA methylation data was funded by the MRC Integrative Epidemiology Unit which is supported by the Medical Research Council (MC_UU_00011/5) and the University of Bristol. PY was supported by a UK Biotechnology and Biological Sciences Research Council and Economic and Social Research Council Research Grant (grant number ES/N000498/1). HELIX: The research leading to these results has received funding from the European Community’s Seventh Framework Programme (FP7/2007-206) under grant agreement no 308333—the HELIX project. Dr Maribel Casas received funding from Instituto de Salud Carlos III (Ministry of Economy and Competitiveness) (MS14/00108). The Norwegian Mother and Child Cohort Study (MoBa) is supported by the Norwegian Ministry of Health and the Ministry of Education and Research, NIH/NIEHS (contract no. N01-ES-75558), and NIH/NINDS (grant no. 1 UO1 NS 047537-01 and grant no. 2 UO1 NS 047537-06A1). The Rhea project was financially supported by European projects, and the Greek Ministry of Health (Program of Prevention of Obesity and Neurodevelopmental Disorders in Preschool Children, in Heraklion district, Crete, Greece: 2011–2014; 'Rhea Plus': Primary Prevention Program of Environmental Risk Factors for Reproductive Health, and Child Health: 2012–2015). The work was also supported by MICINN (MTM2015-68140-R) and Centro Nacional de Genotipado-CEGEN-PRB2-ISCIII. We acknowledge support from the Spanish Ministry of Science, Innovation and Universities through the “Centro de Excelencia Severo Ochoa 2019-2023” Program (CEX2018-000806-S), and support from the Generalitat de Catalunya through the CERCA Program. INMA: Main funding of the epigenetic studies in INMA were grants from Instituto de Salud Carlos III (Red INMA G03/176, CB06/02/0041), Spanish Ministry of Health (FIS-PI04/1436, FIS-PI08/1151 including FEDER funds, FIS-PI11/00610, FIS-FEDER-PI06/0867, FIS-FEDER-PI03-1615) Generalitat de Catalunya-CIRIT 1999SGR 00241, Fundació La marató de TV3 (090430), EU Commission (261357-MeDALL: Mechanisms of the Development of ALLergy), and European Research Council (268479-BREATHE: BRain dEvelopment and Air polluTion ultrafine particles in scHool childrEn). MoBa: The Norwegian Mother, Father and Child Cohort Study are supported by the Norwegian Ministry of Health and Care Services and the Ministry of Education and Research, NIH/NIEHS (contract no N01-ES-75558), NIH/NINDS (grant no.1 UO1 NS 047537-01 and grant no.2 UO1 NS 047537-06A1). For this work, MoBa 1 and 2 were supported by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences (Z01-ES-49019) and the Norwegian Research Council/BIOBANK (grant no 221097). This work was partly supported by the Research Council of Norway through its Centres of Excellence funding scheme, project number 262700. MoBa3 epigenomics data analyses were funded by INCA/Plan Cancer-EVA-INSERM, France, and the International Childhood Cancer Cohort Consortium (I4C), and performed by the Epigenetics Group at the International Agency for Research on Cancer (IARC, Lyon, France) Piccolipiù: Piccolipiù cohort was approved and initially funded by the Italian National Centre for Disease Prevention and Control (CCM grant 2010) and by the Italian Ministry of Health (art 12 and 12bis 502/92). Project Viva: Grants from the US National Institutes of Health (R01 HD034568, UH3 OD023286, R01 HL111108, R01 NR013945). RHEA: Rhea acknowledge all funding sources for the Rhea study: the European Union H2020 (LIFECYCLE), FP7 (HELIX, CHICOS, EnviroGenomarkers, ENRIECO, ESCAPE) and FP6 (HiWate, NewGeneris) programmes. The National Strategic Reference Framework (ESPA) 2007–13, the General Secretariat for Research and Technology in Greece and the Research Committee of the University of Crete, Greece. Funders had no influence of any kind on analyses or results interpretation. ### Author Declarations All relevant ethical guidelines have been followed; any necessary IRB and/or ethics committee approvals have been obtained and details of the IRB/oversight body are included in the manuscript. Yes All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All code used to generate our results is available on our Open Science Framework site at doi:10.17605/OSF.IO/EBTW7. We are not able to publicly share individual level data from participating cohorts due to issues with consent and ethics, however all summary statistics generated by meta-analysis will be available at doi:10.17605/OSF.IO/EBTW7 once this pre-print has been accepted for publication in a peer-reviewed journal. <>
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