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Int J Epidemiol. 2015 Aug;44(4):1199-210. doi: 10.1093/ije/dyv028. Epub 2015 Apr 14.

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

Author information

1
Johns Hopkins Bloomberg School of Public Health, Wendy Klag Center for Autism and Developmental Disabilities, Johns Hopkins University, Center for Epigenetics.
2
Johns Hopkins Bloomberg School of Public Health, Wendy Klag Center for Autism and Developmental Disabilities, Johns Hopkins University, Center for Epigenetics, Johns Hopkins Bloomberg School of Public Health, Epidemiology.
3
Lieber Institute for Brain Development, Johns Hopkins Bloomberg School of Public Health, Mental Health and.
4
Johns Hopkins University, Center for Epigenetics.
5
Johns Hopkins Bloomberg School of Public Health, Wendy Klag Center for Autism and Developmental Disabilities, Johns Hopkins Bloomberg School of Public Health, Epidemiology.
6
George Washington University, Milken Institute School of Public Health, Johns Hopkins Bloomberg School of Public Health.
7
Kaiser Permanente, Division of Research, Autism Research Program.
8
University of California Davis School of Medicine, Public Health Sciences.
9
Drexel University, A.J. Drexel Autism Institute, Drexel University School of Public Health, Epidemiology and Biostatistics.
10
Johns Hopkins Bloomberg School of Public Health, Wendy Klag Center for Autism and Developmental Disabilities, Johns Hopkins Bloomberg School of Public Health, Mental Health and.
11
Johns Hopkins University, Center for Epigenetics, Johns Hopkins University School of Medicine, Medicine.

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.

KEYWORDS:

DNA methylation; Epigenetics; autism risk; sperm

PMID:
25878217
PMCID:
PMC4598797
DOI:
10.1093/ije/dyv028
[Indexed for MEDLINE]
Free PMC Article

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