Mouat Julia S, Krigbaum Nickilou Y, Hakam Sophia, Thrall Emily, Kuodza George E, Mellis Julia, Yasui Dag H, Cirillo Piera M, Ludena Yunin J, Schmidt Rebecca J, La Merrill Michele A, Hertz-Picciotto Irva, Cohn Barbara A, LaSalle Janine M
Department of Medical Microbiology and Immunology, School of Medicine, University of California, Davis, CA, USA.
Perinatal Origins of Disparities Center, University of California, Davis, CA, USA.
Biol Sex Differ. 2025 Apr 30;16(1):30. doi: 10.1186/s13293-025-00712-9.
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.
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.
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).
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.
自闭症谱系障碍（ASD）是一组神经发育疾病，目前通过儿童期行为评估进行诊断，但其神经病理学变化始于子宫内。ASD在男性中更常被诊断出来，这种差异归因于生物学性别差异和诊断偏差。识别分子生物标志物，如DNA甲基化特征，可为新生儿的ASD风险提供更客观的筛查，从而实现早期干预。据报道，在后来被诊断为ASD的新生儿的多个组织中存在表观遗传失调，但这是第一项研究新生儿血液（一种易于获取且广泛储存的组织）中ASD的性别特异性DNA甲基化特征的研究。
我们使用全基因组亚硫酸氢盐测序（WGBS）对ASD个体和正常发育（TD）个体的新生儿血液进行DNA甲基化检测（发现集n = 196，复制集n = 90）。对性别分层的差异甲基化区域（DMR）进行复制评估、性别比较、与其他组织的DMR重叠分析，以及生物过程和SFARI ASD风险基因的富集分析。
我们发现，来自男女两性的新生儿血液ASD DMR在独立队列中显著复制，与TD样本相比，ASD中低甲基化更为富集，且位于启动子、CpG岛和CpG岛岸区。通过比较女性和男性样本，我们发现TD个体中大多数与性别相关的DMR在ASD个体中也存在，同时还有其他ASD特异性性别差异。女性特异性DMR在X染色体位置上富集。在男女两性中，新生儿血液DMR与脐带血和胎盘的DMR有显著重叠，但与死后大脑皮质的DMR无重叠。所有组织的DMR在神经发育过程（女性）和已知ASD基因（男女两性）中均有富集。
总体而言，我们在新生儿血液中识别并复制了ASD的性别特异性DNA甲基化特征，该特征支持女性保护作用，并突出了新生儿中ASD表观遗传和遗传特征的趋同性。尽管该研究存在局限性，特别是女性样本量方面，但我们的结果证明了新生儿血液在ASD筛查中的潜力，并强调了性别分层在未来研究中的重要性。
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