Artificial Neural Networks Reveal Sex Differences in Gene Methylation, and Connections Between Maternal Risk Factors and Symptom Severity in Autism Spectrum Disorder

Abstract

Aim and methods: Artificial neural networks were used to unravel connections among blood gene methylation levels, sex, maternal risk factors and symptom severity evaluated using the Autism Diagnostic Observation Schedule 2 (ADOS-2) score in 58 children with autism spectrum disorder (ASD). Results: Methylation levels of MECP2, HTR1A and OXTR genes were connected to females, and those of EN2, BCL2 and RELN genes to males. High gestational weight gain, lack of folic acid supplements, advanced maternal age, preterm birth, low birthweight and living in rural context were the best predictors of a high ADOS-2 score. Conclusion: Artificial neural networks revealed links among ASD maternal risk factors, symptom severity, gene methylation levels and sex differences in methylation that warrant further investigation in ASD.

Keywords::

• artificial neural networks
• ASD
• autism spectrum disorder
• DNA methylation
• epigenetics
• maternal risk factors
• sex difference

Supplementary data

To view the supplementary data that accompany this paper please visit the journal website at: www.tandfonline.com/doi/suppl/10.2217/epi-2022-0179

Author contributions

F Coppedè conceived and designed the study. S Calderoni, R Cagiano and F Muratori collected the samples and provided clinical data of the patients. R Gallo, S Calderoni and R Cagiano administered the study questionnaire and collected maternal data. A Stoccoro and R Gallo performed DNA methylation experiments. F Coppedè, S Calderoni, L Migliore and F Muratori provided reagents and funds. A Stoccoro prepared the dataset and drafted Table 1 & Supplementary Table 1. E Grossi performed ANN analysis and drafted the figures. F Coppedè interpreted the data and wrote the manuscript. All authors edited the paper and approved the final manuscript.

Financial & competing interests disclosure

The current study was funded by University of Pisa Research Project (PRA 2017 61). Moreover, a grant from the IRCCS Fondazione Stella Maris (Grant Ricerca Corrente, and the ‘5 X 1000’ voluntary contributions, Italian Ministry of Health, no. 2774203) further supported the study. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Editorial Board disclosure

F Coppedè is a member of the Epigenomics Editorial Board. He was not involved in any editorial decisions related to the publication of this article, and all author details were blinded to the article’s peer reviewers as per the journal’s double-blind peer review policy.

Ethical conduct of research

The authors state that they have obtained appropriate institutional review board approval or have followed the principles outlined in the Declaration of Helsinki for all human or animal experimental investigations. In addition, signed informed consent was obtained by parents or legal representatives of the children enrolled in the study.

Additional information

Funding

The current study was funded by University of Pisa Research Project (PRA 2017 61). Moreover, a grant from the IRCCS Fondazione Stella Maris (Grant Ricerca Corrente, and the ‘5 X 1000’ voluntary contributions, Italian Ministry of Health, no. 2774203) further supported the study. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.