Linking genetics to epigenetics: The role of folate and folate‐related pathways in neurodevelopmental disorders

Abstract

There is growing evidence that epigenetic dysregulation plays a role in neurodevelopmental disorders. In humans, folate is one of the main donors of the methyl group required for the synthesis of S-adenosylmethionine, which in turn is needed for DNA and histone methylation as key neurodevelopment processes. Folate deficiency during pregnancy has been correlated with neural tube defects and with a higher incidence of neurocognitive and/or neurobehavioral deficits. A similar outcome may be exerted by gene polymorphisms in folate or folate-related pathways. This has been documented by numerous case/control association studies performed on neurodevelopmental disorders such as autism spectrum disorder and attention deficit hyperactivity disorder. In this regard, the folate cycle represents a "perfect model" of how genetics influences epigenetics. Gene variants in folate and folate-related pathways can be considered risk factors for neurodevelopmental disorders and should therefore be assessed by genetic testing in pregnant women. High-risk women should be considered for folate supplementation during pregnancy. Here, we review all published case/control association studies on gene polymorphisms in folate and folate-related pathways performed on neurodevelopmental disorders, provide an overview of neurodevelopment and DNA methylation changes occurring at this time, and describe the biological basis of neurodevelopmental disorders and recent evidence of their epigenetic dysregulation.

How Lifestyle Factors Affect Cognitive and Executive Function and the Ability to Learn in Children

“…Other micronutrients important for brain development and function are iodine, which has been shown to be critical for normal function of the brain, as demonstrated in a re-pletion study in individuals with iodine insufficiency [88]; and folate, as supplementation during pregnancy significantly decreases the manifestation of neural tube defects [89], and in school-aged children, folate [90] and vitamin B12 [91] intake has been associated with academic performance. Moreover, zinc is essential for normal brain development, playing an essential role in neuronal migration, neurogenesis, and synaptogenesis [92].…”

Maternal Dietary Factors and the Risk of Autism Spectrum Disorders: A Systematic Review of Existing Evidence

“…Evidence of prenatal deficiencies leading to neural tube defects led to widespread fortification in the United States in 1998 and 53 other countries [Crider, Bailey, & Berry, 2011], though insufficiency and deficiency are still common [DeVilbiss et al, 2015; Rogers et al, 2018]. Folate acts as a cofactor in one‐carbon metabolism, particularly in the conversion of homocysteine to S‐adenosyl‐methionine, a key methyl‐donor, and thus plays a critical role in methylation [Mahmoud & Ali, 2019], a process with suspected importance for DNA synthesis and DNA methylation directly related to neurodevelopment [Lintas, 2019; Zeisel, 2011]. Therefore deficiency may result in DNA damage and neuronal death [Mattson & Shea, 2003].…”

“…Sufficient levels of folate are necessary for favorable neurodevelopment in the fetus during the critical windows of preconception and early pregnancy [DeVilbiss et al, 2015; Geiman & Muegge, 2010]. Further details of folate mechanisms have been previously summarized in several systematic reviews and meta‐analyses [Castro et al, 2016; DeVilbiss et al, 2015; Y. Gao, Sheng, et al, 2016; Lintas, 2019; Moretti et al, 2004; Naninck, Stijger, & Brouwer‐Brolsma, 2019; Wang, Li, Zhao, & Li, 2017].…”

“…Further details of folate mechanisms have been previously summarized in several systematic reviews and meta-analyses [Castro et al, 2016;DeVilbiss et al, 2015;Y. Gao, Sheng, et al, 2016;Lintas, 2019;Moretti et al, 2004;Naninck, Stijger, & Brouwer-Brolsma, 2019;Wang, Li, Zhao, & Li, 2017].…”

Early Environmental Exposures and Contaminants: a Design Framework for Biospecimen Collection and Analysis for a Prospective National Birth Cohort

“…Fatty acids accumulate rapidly in the myelin sheath in the last trimester of pregnancy (Martinez, 1992) and early life, with the human placenta differentially selecting arachidonic acid (AA), docosatetraenoic acid (DTA), docosahexaenoic acid (DHA), and other PUFAs for neural development (Crawford et al, 1993). Together, these nutrients have known behavioral and physiological interactions with substance use exposures (Eichner & Hillman, 1973;Flynn et al, 1981;Gabriel et al, 2006;Hadizadeh, Salehi, Bozorgnia, & Ahmadkhaniha, 2020;Milman & Kirchhoff, 1996), contribute to alterations in the epigenome (Lintas, 2019), and impact the immune response (Lynch et al, 2018). Self-reported nutrient consumption is prone to systematic biases, making biomarkers the preferred method of assessment (Kuhnle, 2012).…”