31721
Paternal Sperm DNA Methylation and Offspring 36-Month Outcomes from an Autism-Enriched Cohort

Poster Presentation
Friday, May 3, 2019: 11:30 AM-1:30 PM
Room: 710 (Palais des congres de Montreal)
J. I. Feinberg1, H. E. Volk1, C. Ladd-Acosta1, A. E. Jaffe2, C. J. Newschaffer3,4, I. Hertz-Picciotto5, L. A. Croen6, A. P. Feinberg7 and M. D. Fallin1, (1)Wendy Klag Center for Autism and Developmental Disabilities, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, (2)Lieber Institute for Brain Development, Baltimore, MD, (3)AJ Drexel Autism Institute, Philadelphia, PA, (4)A.J. Drexel Autism Institute, Philadelphia, PA, (5)MIND Institute, University of California, Davis, Sacramento, CA, (6)Division of Research, Kaiser Permanente, Oakland, CA, (7)Johns Hopkins University, Baltimore, MD
Background: There is growing evidence supporting the contributions of both genetic and environmental risk factors for autism spectrum disorder (ASD). Epigenetic marks can reflect both genetic and environmental variation and have been implicated in ASD via multiple lines of evidence. We, and others, have reported DNA methylation associations with ASD and related traits, although the specificity of timing and tissue type (brain, blood, cord blood, placenta, sperm) is still unclear. Sperm is an important tissue for inquiry given its direct connection to germline DNA of the offspring and recent reports on relationships between genetic and paternal environmental experiences and sperm methylation. We previously reported associations between paternal sperm DNA methylation and 12-month ASD-related outcomes (AOSI) in the ASD-enriched risk Early Autism Risk Longitudinal Investigation (EARLI) 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.

See more of: Epigenetics
See more of: Epigenetics