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Children of older fathers carry an increased risk for developing autism and other disorders. To elucidate the underlying mechanisms, we investigated the correlation of sperm DNA methylation with paternal age and its impact on the epigenome of the offspring. Methylation levels of nine candidate genes and  LINE-1  repeats were quantified by bisulfite pyrosequencing in sperm DNA of 162 donors and 191 cord blood samples of resulting children (conceived by IVF/ICSI with the same sperm samples). Four genes showed a significant negative correlation between sperm methylation and paternal age. For  FOXK1  and  KCNA7 , the age effect on the sperm epigenome was replicated in an independent cohort of 188 sperm samples. For  FOXK1 , paternal age also significantly correlated with foetal cord blood (FCB) methylation. Deep bisulfite sequencing and allele-specific pyrosequencing allowed us to distinguish between maternal and paternal alleles in FCB samples with an informative SNP. FCB methylation of the paternal  FOXK1  allele was negatively correlated with paternal age, whereas maternal allele was unaffected by maternal age. Since  FOXK1  duplication has been associated with autism, we studied blood  FOXK1  methylation in 74 children with autism and 41 age-matched controls. The  FOXK1  promoter showed a trend for accelerated demethylation in the autism group. Dual luciferase reporter assay revealed that  FOXK1  methylation influences gene expression. Collectively, our study demonstrates that age-related DNA methylation changes in sperm can be transmitted to the next generation and may contribute to the increased disease risk in offspring of older fathers.

Paternal age effects on sperm FOXK1 and KCNA7 methylation and transmission into the next generation