Genetic and Epigenetic MTHFR Gene Variants in the Mothers of Attention-Deficit/Hyperactivity Disorder Affected Children as Possible Risk Factors for Neurodevelopmental Disorders

Abstract

Aim:To assess promoter methylation levels, gene expression levels and 677C>T/1298A>C genotype and allele frequencies of the MTHFR gene in 45 mothers of attention-deficit/hyperactivity disorder affected child/children(ADHDM) and compare it with age matched healthy control mothers (HCM). Materials & methods: High resolution melting analysis, quantitative real time PCR and PCR-RFLP were performed to assess methylation, gene expression and genotyping, respectively. Significance between ADHDM and HCM was assessed by linear (methylation and gene expression) and logistic regression (genotypes). Results:MTHFR gene expression levels were significantly higher in the ADHDM compared with the HCM group (adj-p < 7.7E-04). No differences in MTHFR promoter methylation level and 677C>T/1298A>C genotype frequencies were detected between ADHDM and HCM. Conclusion:We observed increased MTHFR expression levels not resulting from promoter methylation changes in ADHDM respect to HMC, potentially contributing to the ADHD condition in their children and deserving further investigation.

Keywords::

• 1298A>C polymorphism
• 677C>T polymorphism
• attention-deficit/hyperactivity disorder
• folate deficiency during pregnancy
• MTHFR gene promoter methylation
• MTHFR mRNA expression
• neurodevelopment
• neurodevelopmental disorders

Author contributions

CL was responsible for study conception, design, acquisition of data, main drafting and revision of the manuscript; ISP and FC were responsible for data analysis, drafting and revision of the manuscript; CT for healthy control recruitment and RS and AC were responsible for patient recruitment and clinical assessment; AS and MJH for data analysis.

Acknowledgments

The authors gratefully acknowledge the patients, their family for their cooperation and Chiara Gregorj for helping in recruiting healthy controls.

Financial & competing interest disclosure

This study was funded by the Fund-Raising Office of University Campus Bio-Medico of Rome. 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.

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, informed consent has been obtained from the participants involved.

Additional information

Funding

This study was funded by the Fund-Raising Office of University Campus Bio-Medico of Rome. 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.