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Researchers looked for epigenetic tags at 450,000 locations throughout a dad's genome and sperm, comparing each tag found to sites on the Autism Observation Scale for Infants. Image Credit: Wikipedia

Dad's sperm may hold clues to autism

In a small study of 68 children, Johns Hopkins researchers found on the sperm of the fathers, DNA tags that may have contributed to the condition of their children.

A detailed report of their findings is published online in the International Journal of Epidemiology, April 15, 2015.

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 autism is usually inherited, as the condition tends to run in families. In this study, investigators looked for possible causes not in genes themselves, but in the "epigenetic tags" that help regulate gene 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."

Daniele Fallin, Ph.D., co-lead investigator, Professor and Chair the Department of Mental Health, Bloomberg School of Public Health, Director, Wendy Klag Center for Autism and Developmental Disabilities.

Sperm are not only easier to sample than eggs, they are more susceptible to environmental influences that could alter their DNA tags. So Feinberg and Fallin examined the epigenetic tags on sperm of 44 dads with children with autism. The study enrolled pregnant mothers already having had an autistic child, collecting information as well as biological samples, then added the new baby's father's data, and after birth, the babies' data. Early in the pregnancy, a sperm sample was collected from fathers enrolled in the study. One year after the child was born, the child was assessed for early signs of autism using the Autism Observation Scale for Infants (AOSI).

In the DNA collected from each sperm sample, researchers looked for epigenetic tags at 450,000 different positions throughout that dad's genome. Using the AOSI scores for each child, researchers then compared each tag found to see if it was near a site on the AOSI scale. They found 193 different sites where the presence or absence of a tag was statistically related to the AOSI scales.

When they looked at genes near these 193 sites, they found many were involved in developmental processes, especially neural development.

Of particular interest, four out of 10 sites strongly linked to the AOSI scales were located near genes also linked to Prader-Willi syndrome. Prader-Willi is a genetic disorder sharing some behaviors with autism.

The team will continue their research in a larger study with more families and will also examine the occupations and environmental exposures of dads' in the new study. Currently however, no genetic or epigenetic test is available to assess autism risk using sperm.

Abstract
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)] <0.05 associated with performance on the Autism Observational Scale for Infants (AOSI) at 12 months of age in offspring. The DMRs clustered near genes involved in developmental processes, including many genes in the SNORD family, within the Prader-Willi syndrome gene cluster. These results were consistent among the 75 probes on the Illumina 450K array that cover AOSI-associated DMRs from CHARM. Further, 18 of 75 (24%) 450K array probes showed consistent differences in the cerebellums of autistic individuals compared with controls.

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.

Other authors of the report include Jason Feinberg, Kelly Bakulski and Shannon Brown of the Johns Hopkins Bloomberg School of Public Health; Rakel Trygvadottir 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.

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

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