DNA methylation in paternal sperm may contribute to the risk of children's developing autism, a finding that sheds new light on the etiology of this complex disorder.
Investigators at Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, found almost 200 regions of methylated DNA in the fathers of children at increased risk of developing autism that were significantly associated with performance on a scale assessing autism spectrum disorder (ASD) symptoms at 12 months.
"Many of these regions...were also associated with ASD in cerebellum brain samples," the investigators write. "Further, the genes implicated are enriched for neurodevelopment and include regions implicated in Prader-Willi syndrome."
The research was published online April 14 in the International Journal of Epidemiology.
Gene Snapshot
The study came out of a larger prospective pregnancy study of autism called the Early Autism Risk Longitudinal Investigation (EARLI) and included families with an increased risk for autism because of their already having had a child with ASD.
Although that study focused on mothers and on events that occur to babies in utero, the researchers realized that they could also examine associations between the fathers and the development of autism.
"We thought it was important to get dad's blood samples, but then I thought: 'Well, wouldn't it be even more useful to look at the actual germline pool that the dad is potentially giving to the child through his sperm?," study author M. Daniele Fallin, PhD, director of the Wendy Klag Center for Autism and Developmental Disabilities, at Johns Hopkins Bloomberg School of Public Health, told Medscape Medical News.
Dr Fallin explained that the thinking was that "while dad's blood would be an interesting thing, dad's sperm might be even more interesting because it is directly a snapshot of the genes that he might be giving to children."
"Obviously, it's not exactly the DNA that he gave to this child, because of the sperm turnover rate...but it's pretty close."
The researchers assessed genome-wide DNA methylation in 44 paternal semen samples from the fathers of families enrolled in the EARLI study, performing a number of analyses to look for epigenetic tags at 450,000 sites throughout the genome.
Associations were then examined between sperm DNA methylation and the presence of ASD symptoms at age 12 months in the offspring, as measured on the Autism Observation Scale for Infants (AORSI).
The analysis revealed that there were 193 methylated DNA regions in the paternal sperm that were significantly associated with performance on the AORSI at 12 months.
These included several clusters near genes known to be linked to developmental processes, in particular, genes associated with Prader-Willi syndrome, which shares some behavioral symptoms with ASD.
Semen Testing?
The team also conducted an examination of postmortem human brains from individuals with ASD and from control individuals. Investigators found associations with 75 instances of methylated DNA and 18 that were directly related to AORSI scores and that were present only in the cerebellum of individuals with ASD.
Although the results suggest that there are connections between the genetic tags and autism, Dr Fallin was keen to emphasize that these are preliminary findings in a small sample.
"I'm hesitant to go any further in the interpretation than that at this point, because it really requires additional studies to hone that message to something that you can feel extremely confident about," she said.
"I see this study as an opportunity to highlight how important the concept of epigenetics can be in autism and how it's important to think about parental contributions, both through exposure and through their own genotypes to what happens in autism."
Discussing how the findings could be used in the future, Dr Fallin commented: "Our perspective in doing this research is to understand the fundamental biology of autism, with the goal that if you knew the fundamental biology, you could design prevention or intervention strategies."
She concluded: "I don't think that these data, at least in their current form, argue for a semen test, for example, but what they do argue for is that this may be an avenue to understand autism biology better, so maybe down the road such things are possible."
This work was supported by grants from the National Institute of Environmental Health Sciences and Autism Speaks. The authors have disclosed no relevant financial relationships.
Int J Epidemiol. Published online April 14, 2015. Full text
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Cite this: Father's Sperm Linked to Autism - Medscape - Apr 23, 2015.
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