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Background <p>Autism spectrum disorder (ASD) is a group of neurodevelopmental conditions currently diagnosed through behavioral assessments in childhood, though neuropathological changes begin <i>in utero</i>. ASD is more commonly diagnosed in males, a disparity attributed to both biological sex differences and diagnostic biases. Identifying molecular biomarkers, such as DNA methylation signatures, could provide more objective screening for ASD-risk in newborns, allowing for early intervention. Epigenetic dysregulation has been reported in multiple tissues from newborns who are later diagnosed with ASD, but this is the first study to investigate sex-specific DNA methylation signatures for ASD in newborn blood, an accessible and widely banked tissue.</p> Methods <p>We assayed DNA methylation from newborn blood of ASD and typically developing (TD) individuals (discovery set <i>n</i> = 196, replication set <i>n</i> = 90) using whole genome bisulfite sequencing (WGBS). Sex-stratified differentially methylated regions (DMRs) were assessed for replication, comparisons by sex, overlaps with DMRs from other tissues, and enrichment for biological processes and SFARI ASD-risk genes.</p> Results <p>We found that newborn blood ASD DMRs from both sexes significantly replicated in an independent cohort and were enriched for hypomethylation in ASD compared to TD samples, as well as location in promoters, CpG islands, and CpG island shores. By comparing female to male samples, we found that most sex-associated DMRs in TD individuals were also found in ASD individuals, alongside additional ASD-specific sex differences. Female-specific DMRs were enriched for X chromosomal location. Across both sexes, newborn blood DMRs overlapped significantly with DMRs from umbilical cord blood and placenta but not post-mortem cerebral cortex. DMRs from all tissues were enriched for neurodevelopmental processes (females) and known ASD genes (both sexes).</p> Conclusions <p>Overall, we identified and replicated a sex-specific DNA methylation signature of ASD in newborn blood that supported the female protective effect and highlighted convergence of epigenetic and genetic signatures of ASD in newborns. Despite the study’s limitations, particularly in female sample sizes, our results demonstrate the potential of newborn blood in ASD screening and emphasize the importance of sex-stratification in future studies.</p>

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Sex-specific DNA methylation signatures of autism spectrum disorder from whole genome bisulfite sequencing of newborn blood

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年4月30日

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  • Julia S. Mouat,
  • Nickilou Y. Krigbaum,
  • Sophia Hakam,
  • Emily Thrall,
  • George E. Kuodza,
  • Julia Mellis,
  • Dag H. Yasui,
  • Piera M. Cirillo,
  • Yunin J. Ludena,
  • Rebecca J. Schmidt,
  • Michele A. La Merrill,
  • Irva Hertz-Picciotto,
  • Barbara A. Cohn,
  • Janine M. LaSalle

摘要

Background

Autism spectrum disorder (ASD) is a group of neurodevelopmental conditions currently diagnosed through behavioral assessments in childhood, though neuropathological changes begin in utero. ASD is more commonly diagnosed in males, a disparity attributed to both biological sex differences and diagnostic biases. Identifying molecular biomarkers, such as DNA methylation signatures, could provide more objective screening for ASD-risk in newborns, allowing for early intervention. Epigenetic dysregulation has been reported in multiple tissues from newborns who are later diagnosed with ASD, but this is the first study to investigate sex-specific DNA methylation signatures for ASD in newborn blood, an accessible and widely banked tissue.

Methods

We assayed DNA methylation from newborn blood of ASD and typically developing (TD) individuals (discovery set n = 196, replication set n = 90) using whole genome bisulfite sequencing (WGBS). Sex-stratified differentially methylated regions (DMRs) were assessed for replication, comparisons by sex, overlaps with DMRs from other tissues, and enrichment for biological processes and SFARI ASD-risk genes.

Results

We found that newborn blood ASD DMRs from both sexes significantly replicated in an independent cohort and were enriched for hypomethylation in ASD compared to TD samples, as well as location in promoters, CpG islands, and CpG island shores. By comparing female to male samples, we found that most sex-associated DMRs in TD individuals were also found in ASD individuals, alongside additional ASD-specific sex differences. Female-specific DMRs were enriched for X chromosomal location. Across both sexes, newborn blood DMRs overlapped significantly with DMRs from umbilical cord blood and placenta but not post-mortem cerebral cortex. DMRs from all tissues were enriched for neurodevelopmental processes (females) and known ASD genes (both sexes).

Conclusions

Overall, we identified and replicated a sex-specific DNA methylation signature of ASD in newborn blood that supported the female protective effect and highlighted convergence of epigenetic and genetic signatures of ASD in newborns. Despite the study’s limitations, particularly in female sample sizes, our results demonstrate the potential of newborn blood in ASD screening and emphasize the importance of sex-stratification in future studies.