Epigenetic changes in sperm are associated with paternal and child quantitative autistic traits in an autism-enriched cohort

There is a need to consider paternal contributions to autism spectrum disorder (ASD) more strongly. Autism etiology is complex, and heritability is not explained by genetics alone. Understanding paternal gametic epigenetic contributions to autism could help fill this knowledge gap. In the present study, we explored whether paternal autistic traits, and the sperm epigenome, were associated with autistic traits in children at 36 months enrolled in the Early Autism Risk Longitudinal Investigation (EARLI) cohort. EARLI is a pregnancy cohort that recruited and enrolled pregnant women in the first half of pregnancy who already had a child with ASD. After maternal enrollment, EARLI fathers were approached and asked to provide a semen specimen. Participants were included in the present study if they had genotyping, sperm methylation data, and Social Responsiveness Scale (SRS) score data available. Using the CHARM array, we performed genome-scale methylation analyses on DNA from semen samples contributed by EARLI fathers. The SRS-a 65-item questionnaire measuring social communication deficits on a quantitative scale-was used to evaluate autistic traits in EARLI fathers (n = 45) and children (n = 31). We identified 94 significant child SRS-associated differentially methylated regions (DMRs), and 14 significant paternal SRS-associated DMRs (fwer p < 0.05). Many child SRS-associated DMRs were annotated to genes implicated in ASD and neurodevelopment. Six DMRs overlapped across the two outcomes (fwer p < 0.1), and, 16 DMRs overlapped with previous child autistic trait findings at 12 months of age (fwer p < 0.05). Child SRS-associated DMRs contained CpG sites independently found to be differentially methylated in postmortem brains of individuals with and without autism. These findings suggest paternal germline methylation is associated with autistic traits in 3-year-old offspring. These prospective results for autism-associated traits, in a cohort with a family history of ASD, highlight the potential importance of sperm epigenetic mechanisms in autism.

Automated summary

There is a need to consider the paternal contributions to autism spectrum disorder (ASD) and explore the association between paternal autistic traits, sperm epigenome, and autistic traits in children. This study analyzed the genetic and epigenetic data of fathers and children from the Early Autism Risk Longitudinal Investigation (EARLI) cohort. The results showed significant associations between differentially methylated regions (DMRs) in the sperm epigenome and autistic traits in 3-year-old offspring. These findings highlight the potential importance of sperm epigenetic mechanisms in the development of autism.