Epigenetic Insights into Autism Spectrum Disorder: DNA Methylation Levels of NR3C1, ASCL1 and FOXO3 in Korean Autism Spectrum Disorder Sibling Pairs
Miae Oh1, Nan-He Yoon2, Soon Ae Kim3, Hee Jeong Yoo4,5
1Department of Psychiatry, Kyung Hee University Hospital, Seoul, Korea
2Division of Social Welfare and Health Administration, Wonkwang University, Iksan, Korea
3Department of Pharmacology, School of Medicine, Eulji University, Daejon, Korea
4Department of Psychiatry, Seoul National University Bundang Hospital, Seongnam, Korea
5Department of Psychiatry, Seoul National University College of Medicine, Seoul, Korea
Correspondence to: Hee Jeong Yoo
Department of Psychiatry, Seoul National University Bundang Hospital, Seoul National University College of Medicine, 82 Gumi-ro 173beon-gil, Bundang-gu, Seongnam 13620, Korea
E-mail: hjyoo@snu.ac.kr
ORCID: https://orcid.org/0000-0003-0521-2718

Soon Ae Kim
Department of Pharmacology, School of Medicine, Eulji University, 77 Gyeryong-ro 771beon-gil, Jung-gu, Daejeon 34824, Korea
E-mail: sakim@eulji.ac.kr
ORCID: https://orcid.org/0000-0002-9831-0511
Received: March 22, 2024; Revised: May 13, 2024; Accepted: May 14, 2024; Published online: July 18, 2024.
© The Korean College of Neuropsychopharmacology. All rights reserved.

This is an Open-Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract
Objective: Previous research on autism spectrum disorder (ASD) in Koreans has primarily focused on genetic diversity because of its high heritability. However, the emerging recognition of transgenerational epigenetic changes has recently shifted research attention towards epigenetic perspectives.
Methods: This study investigated the DNA methylation patterns of the promoter regions of candidate genes such as NR3C1, ASCL1, and FOXO3 in blood samples from ASD probands and their unaffected siblings. The analysis included 54 families (ASD proband group: 54; unaffected biological sibling group: 63). The diagnostic process involved screening the probands and their siblings for ASD based on the Diagnostic and Statistical Manual of Mental Disorders 5th edition. Intelligence, social ability, and medical history were thoroughly assessed using various scales and questionnaires. Genomic DNA from blood samples was analyzed using a methylation-sensitive quantitative polymerase chain reaction to examine the DNA methylation status of candidate genes.
Results: Methylation levels in candidate gene promoter regions differed significantly between the proband and sibling groups for all candidate genes. Correlation analysis between the proband and sibling groups revealed strong and significant correlations in NR3C1 and ASCL1 methylation. Additionally, in the analysis of the relationship between DNA and ASD phenotypes, FOXO3 methylation correlated with social quotient in probands, and ASCL1 methylation was associated with nonverbal communication, and daily living skills as measured by the Korean Vineland Adaptive Behavior Scale. Notably, ASCL1 methylation was significantly associated with parental age at pregnancy.
Conclusion: This study proposes DNA methylation of NR3C1, ASCL1, and FOXO3 in peripheral blood samples is a potential epigenetic biomarker of ASD.
Keywords: Autism spectrum disorder; NR3C1; FOXO3; ASCL1; DNA methylation

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