Haplotype-resolved methylomes reveal parent-of-origin DNA methylation imbalance in autism spectrum disorder.

Authors

Lu Xia, Hailiang Guo, Ruiting Liu, Xue Ren, Shaohuai Han, Xu Huang, Ying Peng, Yan Zhu, Yuanfeng Huang, Zhaowei Jiang, Tengfei Zhu, Tengfei Luo, Zhikun Wang, Xun Zhou, Xiaobo Li, Yanping Zhu, Ting Bai, Qi Tian, Zhiqing Hu, Miaojin Zhou, Qian Jiang, Yidong Shen, Jianjun Ou, Yixiao Zhu, Qiao Zhou, Qian Pan, Tianyun Wang, Hui Guo, Beisha Tang, Zhengmao Hu, Jinchen Li, Kun Xia

Published in

Science advances. Volume 12. Issue 25. Pages eaee4069. Jun 19, 2026. Epub Jun 17, 2026.

Abstract

Epigenetic dysregulation plays an essential role in autism spectrum disorder (ASD), but the parent-of-origin effects (POEs) of DNA methylation remain unknown. Here, we applied PacBio HiFi sequencing with haplotype-phased methylation profiling in 124 individuals (31 ASD quartets) to systematically dissect POE-dependent methylation. Comparative analysis of phased methylomes between probands and unaffected siblings identified 114 paternal- and 106 maternal-specific differential methylated cytosines (DMCs), 45 and 46 differential methylated regions (DMRs), and 2425 and 2693 methylation outliers (MOs), respectively. These POE methylation alterations were enriched in ASD-relevant gene categories but exhibited distinct genomic distributions and functional pathways between parental haplotypes. Furthermore, genome-wide parent-of-origin DMR analysis identified 443 allele-specific methylation (ASM) regions, from which we detected 34 differential expression ASMs and 62 ASM outliers, showing pronounced enrichment within PWS/AS locus and ASD-associated genes. Collectively, this study provides a comprehensive evidence of pervasive POE-dependent methylation imbalance and aberrant ASM at imprinting regions underlying ASD pathogenesis, offering insights into epigenetic mechanisms of complex neurodevelopmental disorders.

PMID:
42308296
Bibliographic data and abstract were imported from PubMed on 18 Jun 2026.

Read full publication at:
Please sign in to see all details.

Stats

1-terrible, 9-excellent. How would you rate this publication? Sign in in to submit your rating.

Post a comment

You need to be signed in to post comments. You can sign in here.

Comments

There are no comments yet.