Advanced Paternal Age Impacts Common Loci in the Sperm and Placenta DNA Methylomes

Epidemiological studies have reported an association between advanced paternal age at conception and an increased risk of neurodevelopmental disorders in offspring, such as autism spectrum disorder. Evidence suggests that DNA methylation alterations in spermatozoa of older men may be transmitted to the feto-placental unit and associated with offspring brain development and behavioral differences later in childhood.

We aimed to assess the association of advanced paternal age with DNA methylation alterations in the human placenta and compare the results to previous findings in spermatozoa.

For this study, 64 placenta samples from the Design, Develop, and Discover (3D) prospective birth cohort study were categorized based on paternal age at conception. DNA methylation of the placenta was interrogated using the Illumina 850K array. There were no differentially methylated sites found to be statistically significant after correction for multiple comparisons, therefore sites with significant nominal p values < 0.05 were assessed and used to define differentially methylated regions (DMRs) associated with genes.

Advanced paternal age was associated with DNA methylation alterations in the placenta at up to 688 genes, with a predominance of hypomethylation (65%), including at eight imprinted loci. About 7% of genes with age-associated DNA methylation changes in placenta overlapped with genes previously reported to show altered DNA methylation in spermatozoa of older men; seven genes common to placenta and spermatozoa had previously been identified in association with susceptibility to autism spectrum disorder. Among loci most affected, we found evidence of sex-specific hypermethylation at genes linked to neurodevelopment (GRM7, EBF3, FOXG1).

Our findings suggest that advanced paternal age at conception correlates with altered DNA methylation at a small number of loci in the human placenta, notably affecting genes involved in neurodevelopment. This study highlights the use of the placenta DNA methylome as a surrogate marker for the potential impact of advanced paternal age on the child.