Haplotype-resolved methylomes reveal parent-of-origin DNA methylation imbalance in autism spectrum disorder
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.
Authors
- Jianjun Ou (ORCID: https://orcid.org/0000-0002-0611-7715)
- Yanping Zhu (ORCID: https://orcid.org/0000-0002-2955-6585)
- Hui Guo (ORCID: https://orcid.org/0000-0002-1570-2545)
- Yan Zhu (ORCID: https://orcid.org/0000-0002-8237-7623)
- Lu Xia (ORCID: https://orcid.org/0000-0003-2450-1320)
- Kun Xia (ORCID: https://orcid.org/0000-0001-8090-6002)
- Xu Huang (ORCID: https://orcid.org/0000-0001-6706-199X)
- Miaojin Zhou (ORCID: https://orcid.org/0000-0002-6636-6000)
- Tengfei Luo (ORCID: https://orcid.org/0000-0003-3940-8786)
- Ting Bai (ORCID: https://orcid.org/0000-0001-8337-3272)
- Qi Tian (ORCID: https://orcid.org/0000-0003-0798-2759)
- Hailiang Guo
- Jinchen Li (ORCID: https://orcid.org/0000-0001-5522-806X)
- Ying Peng (ORCID: https://orcid.org/0000-0002-7760-0317)
- X L Li
- Beisha Tang (ORCID: https://orcid.org/0000-0003-2120-1576)
- Lina Zhu (ORCID: https://orcid.org/0000-0002-8558-2120)
- Zi Wang (ORCID: https://orcid.org/0000-0002-3953-0493)
- Qiao Zhou (ORCID: https://orcid.org/0000-0001-5929-5438)
- Qi Pan (ORCID: https://orcid.org/0000-0001-6580-2731)
- Zhiqing Hu (ORCID: https://orcid.org/0000-0002-3334-2002)
- Tianyun Wang (ORCID: https://orcid.org/0000-0002-5179-087X)
- Shaohuai Han (ORCID: https://orcid.org/0009-0005-2186-1074)
- Y Huang (ORCID: https://orcid.org/0009-0005-3406-4875)
- Zhaowei Jiang
- Ruiting Liu
- Tengfei Zhu
- Yidong Shen
- Zhengmao Hu (ORCID: https://orcid.org/0009-0004-4181-5692)
- Xun Zhou (ORCID: https://orcid.org/0009-0005-8738-1081)
- Qian Jiang
- Xue Ren (ORCID: https://orcid.org/0009-0006-4227-7368)
Institutions
- Central South University (CN)
- Changsha Medical University (CN)
- Peking University (CN)
- Hunan Provincial Center for Disease Control and Prevention (CN)
- National Clinical Research (US)
- Annoroad Gene Technology (China) (CN)
- First Affiliated Hospital of University of South China (CN)
- Second Xiangya Hospital of Central South University (CN)
- Xiangya Hospital Central South University (CN)
- University of South China (CN)
Publication Details
- Journal
- Science Advances
- Published
- 2026-06-17
- DOI
- https://doi.org/10.1126/sciadv.aee4069
- Primary Topic
- Autism Spectrum Disorder Research
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- National Natural Science Foundation of China