Evidence map›Paper›PMID 40307894›Full record

ArticleBiology of sex differences2025

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

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 and 4 more

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PubMed Full text at PMC Publisher
In one paragraph

Article in Biology of sex differences, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 6 papers, 1 of them a synthesis that pooled it.

0numbers the graph read from it
0cells of the map it votes in
6citing papers in PubMed, 1 pooled it
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

6 citing papers in PubMed, 1 synthesis or guideline pooled it.

  1. Does the Extreme Male Brain Hypothesis of Autism Apply More to Females Than Males? A Systematic and Meta-Analytic Approach.Autism research : official journal of the International Society for Autism Research · 2026
    Pooled it
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4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

14 authors.

Julia S MouatDepartment of Medical Microbiology and Immunology, School of Medicine, University of California, Davis, CA, USA.
Nickilou Y KrigbaumChild Health and Development Studies, Public Health Institute, Berkeley, CA, USA.
Sophia HakamDepartment of Medical Microbiology and Immunology, School of Medicine, University of California, Davis, CA, USA.
Emily ThrallDepartment of Medical Microbiology and Immunology, School of Medicine, University of California, Davis, CA, USA.
George E KuodzaDepartment of Medical Microbiology and Immunology, School of Medicine, University of California, Davis, CA, USA.
Julia MellisDepartment of Medical Microbiology and Immunology, School of Medicine, University of California, Davis, CA, USA.
Dag H YasuiDepartment of Medical Microbiology and Immunology, School of Medicine, University of California, Davis, CA, USA.
Piera M CirilloChild Health and Development Studies, Public Health Institute, Berkeley, CA, USA.
Yunin J LudenaMIND Institute, University of California, Davis, CA, USA.
Rebecca J SchmidtPerinatal Origins of Disparities Center, University of California, Davis, CA, USA.
Michele A La MerrillPerinatal Origins of Disparities Center, University of California, Davis, CA, USA.
Irva Hertz-PicciottoPerinatal Origins of Disparities Center, University of California, Davis, CA, USA.
Barbara A CohnChild Health and Development Studies, Public Health Institute, Berkeley, CA, USA.
Janine M LaSalleDepartment of Medical Microbiology and Immunology, School of Medicine, University of California, Davis, CA, USA. jmlasalle@ucdavis.edu.

Funding

UC Davis Environmental Health Sciences Core CenterP30ES023513 · NIEHS · UNIVERSITY OF CALIFORNIA AT DAVIS · PI Irva Hertz-Picciotto · 2015 to 2026
$26.0M
PCB Epigenomic Brain & Behavior Lasting Effects Study (PEBBLES)R01ES029213 · NIEHS · UNIVERSITY OF CALIFORNIA AT DAVIS · PI Janine M LaSalle, Pamela J Lein · 2018 to 2026
$6.5M
BUILDS MARBLES: Biorepository Upkeep and Infrastructure for Longitudinal Data Sharing for MARBLESR24ES028533 · NIEHS · UNIVERSITY OF CALIFORNIA AT DAVIS · PI Brittany D. Chambers Butcher, Rebecca Jean Schmidt · 2017 to 2026
$2.3M
BUILDS MARBLES: Biorepository Upkeep and Infrastructure for Longitudinal Data Sharing for MARBLESU24ES028533 · NIEHS · UNIVERSITY OF CALIFORNIA AT DAVIS · PI CHAMBERS BUTCHER, BRITTANY D., SCHMIDT, REBECCA JEAN · 2023 to 2025
$1.2M
Congressionally Directed Medical Research Programs W81XWH-16-1-0254NIEHS NIH HHS P30 ES023513NIEHS NIH HHS R01 ES029213NIEHS NIH HHS R24 ES028533NIEHS NIH HHS U24 ES028533NIH HHS P30 ES023513NIH HHS R01 ES029213
6 · The paper itself

Abstract

backgroundAutism 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.

methodsWe 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.

resultsWe 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).

conclusionsOverall, 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.

Indexed as

Autism Spectrum DisorderDNA MethylationSex CharacteristicsEpigenesis, GeneticFemaleHumansInfant, NewbornMaleWhole Genome SequencingAutism spectrum disorderDifferentially methylated regionsDNA methylationEpigeneticsFemale protective effectNewborn bloodNewborn dried blood spotsSex differencesWhole genome bisulfite sequencingX chromosome

Identifiers

PMID40307894
PMCPMC12042393

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LicenceCC BY
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Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.