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

Jason I. Feinberg, Kelly M. Bakulski, Andrew E. Jaffe, Rakel Tryggvadottir, Shannon C. Brown, Lynn R. Goldman, Lisa A. Croen, Irva Hertz-Picciotto, Craig J. Newschaffer, M. Daniele Fallin, Andrew P. Feinberg

Research output: Contribution to journalArticle

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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 postmortem 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.

Original languageEnglish (US)
Pages (from-to)1199-1210
Number of pages12
JournalInternational journal of epidemiology
Volume44
Issue number4
DOIs
StatePublished - Aug 2015

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DNA Methylation
Autistic Disorder
Spermatozoa
Epigenomics
Prader-Willi Syndrome
Cerebellum
Observation
Symptom Assessment
Multigene Family
Semen
Fathers
Methylation
Genes
Genome
Pregnancy
Autism Spectrum Disorder
Brain

All Science Journal Classification (ASJC) codes

  • Epidemiology

Cite this

Feinberg, J. I., Bakulski, K. M., Jaffe, A. E., Tryggvadottir, R., Brown, S. C., Goldman, L. R., ... Feinberg, A. P. (2015). Paternal sperm DNA methylation associated with early signs of autism risk in an autism-enriched cohort. International journal of epidemiology, 44(4), 1199-1210. https://doi.org/10.1093/ije/dyv028
Feinberg, Jason I. ; Bakulski, Kelly M. ; Jaffe, Andrew E. ; Tryggvadottir, Rakel ; Brown, Shannon C. ; Goldman, Lynn R. ; Croen, Lisa A. ; Hertz-Picciotto, Irva ; Newschaffer, Craig J. ; Daniele Fallin, M. ; Feinberg, Andrew P. / Paternal sperm DNA methylation associated with early signs of autism risk in an autism-enriched cohort. In: International journal of epidemiology. 2015 ; Vol. 44, No. 4. pp. 1199-1210.
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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 postmortem 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.",
author = "Feinberg, {Jason I.} and Bakulski, {Kelly M.} and Jaffe, {Andrew E.} and Rakel Tryggvadottir and Brown, {Shannon C.} and Goldman, {Lynn R.} and Croen, {Lisa A.} and Irva Hertz-Picciotto and Newschaffer, {Craig J.} and {Daniele Fallin}, M. and Feinberg, {Andrew P.}",
year = "2015",
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Feinberg, JI, Bakulski, KM, Jaffe, AE, Tryggvadottir, R, Brown, SC, Goldman, LR, Croen, LA, Hertz-Picciotto, I, Newschaffer, CJ, Daniele Fallin, M & Feinberg, AP 2015, 'Paternal sperm DNA methylation associated with early signs of autism risk in an autism-enriched cohort', International journal of epidemiology, vol. 44, no. 4, pp. 1199-1210. https://doi.org/10.1093/ije/dyv028

Paternal sperm DNA methylation associated with early signs of autism risk in an autism-enriched cohort. / Feinberg, Jason I.; Bakulski, Kelly M.; Jaffe, Andrew E.; Tryggvadottir, Rakel; Brown, Shannon C.; Goldman, Lynn R.; Croen, Lisa A.; Hertz-Picciotto, Irva; Newschaffer, Craig J.; Daniele Fallin, M.; Feinberg, Andrew P.

In: International journal of epidemiology, Vol. 44, No. 4, 08.2015, p. 1199-1210.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Paternal sperm DNA methylation associated with early signs of autism risk in an autism-enriched cohort

AU - Feinberg, Jason I.

AU - Bakulski, Kelly M.

AU - Jaffe, Andrew E.

AU - Tryggvadottir, Rakel

AU - Brown, Shannon C.

AU - Goldman, Lynn R.

AU - Croen, Lisa A.

AU - Hertz-Picciotto, Irva

AU - Newschaffer, Craig J.

AU - Daniele Fallin, M.

AU - Feinberg, Andrew P.

PY - 2015/8

Y1 - 2015/8

N2 - 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 postmortem 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.

AB - 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 postmortem 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.

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