Age-specific DNA methylation alterations in sperm at imprint control regions may contribute to the risk of autism spectrum disorder in offspring.

This study looked at how a father's age might affect autism risk in their children through changes in sperm. Researchers found that as men get older, chemical markers on their sperm DNA change in ways that could influence brain development in their future children. While the changes were small, they occurred in important genetic regions that control how genes work. This research helps explain why older fathers may have a slightly higher chance of having children with autism.

This epigenome-wide association study examined sperm DNA methylation patterns in 63 men to understand how paternal age may contribute to autism spectrum disorder (ASD) risk in offspring. Researchers identified 14,622 age-related changes in DNA methylation, with 69% showing inverse correlations with age. Of particular interest were 747 methylation changes near imprint control regions (ICRs) of 95 imprinted genes. These ICRs regulate gene expression and their disruption may contribute to neurodevelopmental disorders in children.

Several imprinted genes linked to ASD were identified, though the study notes that methylation effect sizes were subtle. The findings suggest that age-related epigenetic changes in sperm may contribute to ASD complexity and heterogeneity.

Findings suggest paternal age-related epigenetic changes in sperm may contribute to ASD risk, supporting delayed fatherhood as a consideration in family planning. However, effect sizes are small and population-level impacts unclear. Results support development of educational programs about paternal age effects on offspring health.

Small sample size of 63 men limits generalizability. Methylation effect sizes were subtle, and the study design cannot establish causation. The abstract does not specify whether men were fathers of autistic children or controls, limiting interpretation of clinical relevance.

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:,andFurther 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.