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.
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.
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.
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.
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.
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.
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