Epigenetic insights into ASD: DNA methylation levels of NR3C1, ASCL1 and FOXO3 in Korean ASD sibling pairs
Miae Oh 1, Nan Yoon 2, Soon Ae Kim 3, Hee Jeong Yoo 4, 5*
1Department of Psychiatry, Kyung Hee University Hospital, Seoul, South Korea, 2Division of Social Welfare and Health Administration, Wonkwang University, Iksan, South Korea , 3Department of Pharmacology, School of Medicine, Eulji University, Daejon, South Korea, 4Department of Psychiatry, Seoul National University Bundang Hospital, Seongnam, South Korea , 5Seoul National University College of Medicine, Seoul, South Korea
Received: March 16, 2024; Revised: May 13, 2024; Accepted: May 14, 2024; Published online: May 14, 2024.
© The Korean College of Neuropsychopharmacology. All rights reserved.

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 DSM-5. 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 (SQ) in probands, and ASCL1 methylation was associated with nonverbal communication, and daily living skills as measured by the Vineland Adaptive Behavior Scale (K-VABS). 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