Paternal Sperm May Hold Clues to Autism

Tags on DNA from fathers’ sperm linked to children’s autism symptoms.

In a small study, Johns Hopkins researchers found that DNA from the sperm of men whose children had early signs of autism shows distinct patterns of regulatory tags that could contribute to the condition. A detailed report of their findings will be published online in the International Journal of Epidemiology on April 15.

Autism spectrum disorder (autism) affects one in 68 children in the U.S. Although studies have identified some culprit genes, most cases remain unexplained. But most experts agree that autism is usually inherited, since the condition tends to run in families. In this study, investigators looked for possible causes for the condition not in genes themselves, but in the “epigenetic tags” that help regulate genes’ activity.

“We wondered if we could learn what happens before someone gets autism,” says Andrew Feinberg, M.D., M.P.H., the King Fahd Professor of Molecular Medicine and director of the Center for Epigenetics at the Johns Hopkins University School of Medicine. “If epigenetic changes are being passed from fathers to their children, we should be able to detect them in sperm,” adds co-lead investigator Daniele Fallin, Ph.D., professor and chair of the Department of Mental Health in the Bloomberg School of Public Health and director of the Wendy Klag Center for Autism and Developmental Disabilities.

In addition to being easier to sample than egg cells from women, sperm are more susceptible to environmental influences that could alter the epigenetic tags on their DNA. Feinberg, Fallin and their team assessed the epigenetic tags on DNA from sperm from 44 dads. The men were part of an ongoing study to assess the factors that influence a child early on, before he or she is diagnosed with autism. The study enrolls pregnant mothers who already have a child with autism and collects information and biological samples from these mothers, the new baby’s father and the babies themselves after birth. Early in the pregnancy, a sperm sample was collected from fathers enrolled in the study. One year after the child was born, he or she was assessed for early signs of autism using the Autism Observation Scale for Infants (AOSI).

This shows the sperm and egg fusing.

In addition to being easier to sample than egg cells from women, sperm are more susceptible to environmental influences that could alter the epigenetic tags on their DNA. The image is for illustrative purposes only.

The researchers collected DNA from each sperm sample and looked for epigenetic tags at 450,000 different positions throughout the genome. They then compared the likelihood of a tag being in a particular site with the AOSI scores of each child. They found 193 different sites where the presence or absence of a tag was statistically related to the AOSI scores.

When they looked at which genes were near the identified sites, they found that many of them were close to genes involved in developmental processes, especially neural development. Of particular interest was that four of the 10 sites most strongly linked to the AOSI scores were located near genes linked to Prader-Willi syndrome, a genetic disorder that shares some behavioral symptoms with autism. Several of the altered epigenetic patterns were also found in the brains of individuals with autism, giving credence to the idea that they might be related to autism.

The team plans to confirm its results in a study of more families and to look at the occupations and environmental exposures of the dads involved. There is currently no genetic or epigenetic test available to assess autism risk.

About this autism research

Other authors of the report include Jason Feinberg, Kelly Bakulski and Shannon Brown of the Johns Hopkins Bloomberg School of Public Health; Rakel Tryggvadottir of The Johns Hopkins University; Andrew Jaffe of the Lieber Institute for Brain Development; Lynn Goldman of The George Washington University; Lisa Croen of Kaiser Permanente; Irva Hertz-Picciotto of the University of California, Davis; and Craig Newschaffer of Drexel University.

Funding: This work was supported by grants from the National Institute of Environmental Health Sciences (R01 ES017646, R01 ES16443) and Autism Speaks.

Source: Catherine Kolf – Johns Hopkins Medicine
Image Source: The image is in the public domain
Original Research: Abstract for “Paternal sperm DNA methylation associated with early signs of autism risk in an autism-enriched cohort” by Feinberg, J. I., Bakulski, K. M., Jaffe, A. E., Tryggvadottir, R., Brown, S. C., Goldman, L. R., Croen, L. A., Hertz-Picciotto, I., Newschaffer, C. J., Daniele Fallin, M., and Feinberg, A. P.y in International Journal of Epidemiology. Published online April 15 2015 doi:10.1093/ije/dyv028


Abstract

Paternal sperm DNA methylation associated with early signs of autism risk in an autism-enriched cohort

Background: Epigenetic mechanisms such as altered DNA methylation have been suggested to play a role in autism, beginning with the classical association of Prader-Willi syndrome, an imprinting disorder, with autistic features.

Objectives: Here we tested for the relationship of paternal sperm DNA methylation with autism risk in offspring, examining an enriched-risk cohort of fathers of autistic children.

Methods: We examined genome-wide DNA methylation (DNAm) in paternal semen biosamples obtained from an autism spectrum disorder (ASD) enriched-risk pregnancy cohort, the Early Autism Risk Longitudinal Investigation (EARLI) cohort, to estimate associations between sperm DNAm and prospective ASD development, using a 12-month ASD symptoms assessment, the Autism Observation Scale for Infants (AOSI). We analysed methylation data from 44 sperm samples run on the CHARM 3.0 array, which contains over 4 million probes (over 7 million CpG sites), including 30 samples also run on the Illumina Infinium HumanMethylation450 (450K) BeadChip platform (∼485 000 CpG sites). We also examined associated regions in an independent sample of post-mortem human brain ASD and control samples for which Illumina 450K DNA methylation data were available.

Results: Using region-based statistical approaches, we identified 193 differentially methylated regions (DMRs) in paternal sperm with a family-wise empirical P-value [family-wise error rate (FWER)]

Conclusions: These data suggest that epigenetic differences in paternal sperm may contribute to autism risk in offspring, and provide evidence that directionally consistent, potentially related epigenetic mechanisms may be operating in the cerebellum of individuals with autism.

“Paternal sperm DNA methylation associated with early signs of autism risk in an autism-enriched cohort” by Feinberg, J. I., Bakulski, K. M., Jaffe, A. E., Tryggvadottir, R., Brown, S. C., Goldman, L. R., Croen, L. A., Hertz-Picciotto, I., Newschaffer, C. J., Daniele Fallin, M., and Feinberg, A. P.y in International Journal of Epidemiology. Published online April 15 2015 doi:10.1093/ije/dyv028

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