Research Paper Volume 17, Issue 12 pp 2950—2988
Age-specific DNA methylation alterations in sperm at imprint control regions may contribute to the risk of autism spectrum disorder in offspring
- 1 Department of Human Genetics, Epigenetic Epidemiology Lab, Faculty of Medicine, KU Leuven, University of Leuven, Leuven 3000, Belgium
- 2 Department II of Internal Medicine, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne 50937, Germany
- 3 Center for Molecular Medicine Cologne (CMMC), Cologne 50931, Germany
- 4 Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne and University Hospital Cologne, Cologne 50931, Germany
- 5 Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, Duke University Medical Center, Durham, NC 27701, USA
- 6 Department of Biological Sciences, Center for Human Health and the Environment, North Carolina State University, Raleigh, NC 27633, USA
- 7 Department of Obstetrics and Gynecology, Division of Reproductive Sciences, Duke University Medical Center, Durham, NC 27701, USA
Received: July 25, 2025 Accepted: December 4, 2025 Published: December 29, 2025
https://doi.org/10.18632/aging.206348How to Cite
Copyright: © 2025 Casella et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Abstract
Research findings suggest that advanced paternal age is associated with an increased risk of autism spectrum disorder (ASD) in children. The biological process behind this father-to-child inheritance of a disease may be driven by sperm epigenetic marks. This has been suggested earlier, but the identification of epigenomic regions responsible for these age-related responses have not been further elaborated. To identify sperm-specific marks, we conducted an epigenome-wide association study in sperm from 63 men, using the Illumina 450K array. Linear regression modeling was applied to identify differentially methylated CpGs (DMCs) by age; we controlled for body mass index, patient status, and multiple testing. We found 14,622 statistically significant age-related DMCs; most (69%) were inversely correlated. We identified 95 imprinted genes and emphasized 747 age-related DMCs adjacent to an imprint control region (ICR). Altered methylation patterns in ICRs may result in disturbed expression of imprinted genes and are suspected to be at the origin of several diseases in offspring, including neurodevelopmental disorders. Mapping our results to other databases revealed the following set of imprinted genes linked to ASD: OTX1, PRDM16, PTPRN2, B4GALNT4, KCNQ1, KCNQ1OT1, DLGAP2, PLAGL1, GNAS, GRB10, MAGEL2, CDH24, and FBRSL1. Further research on these genes could help understand the contribution of paternal age on the development of autism. A change in DNA methylation levels in ICRs before conception may contribute to the heterogeneity and complexity of ASD. Measured DNA methylation effect sizes were subtle, but small epigenetic disturbances in sperm may be important on a population level, especially if men continue delaying fatherhood. Public health would benefit from the development of preventive and educational programs.
Abbreviations
ASD: Autism Spectrum Disorders; BH: Benjamini-Hochberg; BMIQ: Beta Mixture Quantile; DMC: Differentially Methylation CpG Site; FM: Fully Methylated; GO: Gene Ontology; HM: Hemi-methylated; ICR: Imprint Control Region; SFARI: Simons Foundation Autism Reference Initiative; SNP: Single Nucleotide Polymorphisms; TIEGER: The Influence of the Environment on Gametic Epigenetic Reprogramming; UM: Unmethylated.