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Fathers' preconception smoking and offspring DNA methylation

Fathers' preconception smoking and offspring DNA methylation

Title: Fathers' preconception smoking and offspring DNA methylation
Author: Kitaba, Negusse Tadesse
Knudsen, Gerd Toril Mørkve
Johannessen, Ane
Rezwan, Faisal I
Malinovschi, Andrei
Oudin, Anna
Benediktsdóttir, Bryndís
Martino, David
González, Francisco Javier Callejas
Gómez, Leopoldo Palacios
... 10 more authors Show all authors
Date: 2023-08-31
Language: English
Scope: 131
School: Health Sciences
Department: Faculty of Medicine
Other departments
Series: Clinical Epigenetics; 15(1)
ISSN: 1868-7075
DOI: https://doi.org/10.1186/s13148-023-01540-7
Subject: DNA methylation; Epigenetic; Epigenome-wide association study; Paternal effects; Preconception; RHINESSA; Tobacco smoke; Genetics (clinical); Genetics; Molecular Biology; Developmental Biology
URI: https://hdl.handle.net/20.500.11815/4464

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Kitaba , N T , Knudsen , G T M , Johannessen , A , Rezwan , F I , Malinovschi , A , Oudin , A , Benediktsdóttir , B , Martino , D , González , F J C , Gómez , L P , Holm , M , Jõgi , N O , Dharmage , S C , Skulstad , S M , Watkins , S H , Suderman , M , Gómez-Real , F , Schlünssen , V , Svanes , C & Holloway , J W 2023 , ' Fathers' preconception smoking and offspring DNA methylation ' , Clinical Epigenetics , vol. 15 , no. 1 , 131 , pp. 131 . https://doi.org/10.1186/s13148-023-01540-7


Background: Experimental studies suggest that exposures may impact respiratory health across generations via epigenetic changes transmitted specifically through male germ cells. Studies in humans are, however, limited. We aim to identify epigenetic marks in offspring associated with father’s preconception smoking. Methods: We conducted epigenome-wide association studies (EWAS) in the RHINESSA cohort (7–50 years) on father’s any preconception smoking (n = 875 offspring) and father’s pubertal onset smoking < 15 years (n = 304), using Infinium MethylationEPIC Beadchip arrays, adjusting for offspring age, own smoking and maternal smoking. EWAS of maternal and offspring personal smoking were performed for comparison. Father’s smoking-associated dmCpGs were checked in subpopulations of offspring who reported no personal smoking and no maternal smoking exposure. Results: Father’s smoking commencing preconception was associated with methylation of blood DNA in offspring at two cytosine-phosphate-guanine sites (CpGs) (false discovery rate (FDR) < 0.05) in PRR5 and CENPP. Father’s pubertal onset smoking was associated with 19 CpGs (FDR < 0.05) mapped to 14 genes (TLR9, DNTT, FAM53B, NCAPG2, PSTPIP2, MBIP, C2orf39, NTRK2, DNAJC14, CDO1, PRAP1, TPCN1, IRS1 and CSF1R). These differentially methylated sites were hypermethylated and associated with promoter regions capable of gene silencing. Some of these sites were associated with offspring outcomes in this cohort including ever-asthma (NTRK2), ever-wheezing (DNAJC14, TPCN1), weight (FAM53B, NTRK2) and BMI (FAM53B, NTRK2) (p < 0.05). Pathway analysis showed enrichment for gene ontology pathways including regulation of gene expression, inflammation and innate immune responses. Father’s smoking-associated sites did not overlap with dmCpGs identified in EWAS of personal and maternal smoking (FDR < 0.05), and all sites remained significant (p < 0.05) in analyses of offspring with no personal smoking and no maternal smoking exposure. Conclusion: Father’s preconception smoking, particularly in puberty, is associated with offspring DNA methylation, providing evidence that epigenetic mechanisms may underlie epidemiological observations that pubertal paternal smoking increases risk of offspring asthma, low lung function and obesity.


Funding Information: Coordination of the RHINESSA study has received funding from the Research Council of Norway (Grants Nos. 274767, 214123, 228174, 230827 and 273838), ERC StG project BRuSH #804199, the European Union's Horizon 2020 research and innovation programme under grant agreement No. 633212 (the ALEC Study), the Bergen Medical Research Foundation and the Western Norwegian Regional Health Authorities (Grants Nos. 912011, 911892 and 911631). Study centres have further received local funding from the following: Bergen: the above grants for study establishment and coordination, and, in addition, World University Network (REF and Sustainability grants), Norwegian Labour Inspection and the Norwegian Asthma and Allergy Association. Albacete and Huelva: Sociedad Española de Patología Respiratoria (SEPAR) Fondo de Investigación Sanitaria (FIS PS09). Gøteborg, Umeå and Uppsala: the Swedish Heart and Lung Foundation, the Swedish Asthma and Allergy Association. Reykjavik: Iceland University. Melbourne: National Health and Medical Research Council (NHMRC) of Australia (research grants 299901 and 1021275). Tartu: the Estonian Research Council (Grant No. PUT562). Århus: The Danish Wood Foundation (Grant No. 444508795), the Danish Working Environment Authority (Grant No. 20150067134), Aarhus University (PhD scholarship). ALSPAC funding: EPIC arrays age 15–17, John Templeton Foundation (60828) and EPIC arrays age 24, MRC (MC_UU_12013/2) & CLOSER (MRC and ESRC). Publisher Copyright: © 2023, BioMed Central Ltd., part of Springer Nature.

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