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Paternal Sperm DNA Methylation and Offspring 36-Month Outcomes from an Autism-Enriched Cohort
Objectives: We have now examined the associations between paternal sperm DNA methylation and three ASD-related quantitative outcomes at 36 months in the same EARLI sample.
Methods: We performed comprehensive genome-scale methylation analyses on DNA derived from semen samples contributed by 50 fathers enrolled in EARLI. Methylation was measured via the CHARM 3.0 array, which contains over 4 million probes and covers over 7 million CpG sites. We used a region-based approach to identify differentially methylated regions (DMRs) in paternal sperm genomes sampled prior to birth that associated with 36-month offspring scores on: the Mullen Scales of Early Learning (MSEL; 40 subjects), the Social Responsiveness Scale (SRS; 32 subjects), and the Vineland Adaptive Behavior Scales (VABS; 36 subjects). In addition to exploring relevant gene ontology for the associated regions, we identify regions that overlap across each of the 36-month assessments and also across the 193 DMRs previously associated with the Autism Observation Scale for Infants (AOSI) at 12-months in the same cohort.
Results: We identified 50 DMRs in the paternal sperm genome associated with MSEL, 154 sperm DMRs for SRS, and 67 sperm DMRs for the VABS at genome-wide significance (FWER p <0.05); 25 DMRs overlap across at least two outcomes. Developmental outcome-associated DMRs include genes previously associated with ASD (e.g. WWOX, SALL3) and also overlap with DMRs previously reported to be associated with 12-month AOSI scores in the same EARLI sample.
Conclusions: These findings suggest paternal germ-line methylation around the time of pregnancy is associated with offspring cognitive and adaptive functioning in early development up to 3 years later. These prospective results for autism-associated traits, in an enriched familial risk sample, highlight the potential importance of sperm-based epigenetic mechanisms in ASD and neurodevelopment.