Expression Changes in Epigenetic Gene Pathways Associated With One‐Carbon Nutritional Metabolites in Maternal Blood From Pregnancies Resulting in Autism and Non‐Typical Neurodevelopment

Abstract

The prenatal period is a critical window for the development of autism spectrum disorder (ASD). The relationship between prenatal nutrients and gestational gene expression in mothers of children later diagnosed with ASD or non‐typical development (Non‐TD) is poorly understood. Maternal blood collected prospectively during pregnancy provides insights into the effects of nutrition, particularly one‐carbon metabolites, on gene pathways and neurodevelopment. Genome‐wide transcriptomes were measured with microarrays in 300 maternal blood samples in Markers of Autism Risk in Babies‐Learning Early Signs. Sixteen different one‐carbon metabolites, including folic acid, betaine, 5′‐methyltretrahydrofolate (5‐MeTHF), and dimethylglycine (DMG) were measured. Differential expression analysis and weighted gene correlation network analysis (WGCNA) were used to compare gene expression between children later diagnosed as typical development (TD), Non‐TD and ASD, and to one‐carbon metabolites. Using differential gene expression analysis, six transcripts (TGR‐AS1, SQSTM1, HLA‐C, and RFESD) were associated with child outcomes (ASD, Non‐TD, and TD) with genome‐wide significance. Genes nominally differentially expressed between ASD and TD significantly overlapped with seven high confidence ASD genes. WGCNA identified co‐expressed gene modules significantly correlated with 5‐MeTHF, folic acid, DMG, and betaine. A module enriched in DNA methylation functions showed a suggestive protective association with folic acid/5‐MeTHF concentrations and ASD risk. Maternal plasma betaine and DMG concentrations were associated with a block of co‐expressed genes enriched for adaptive immune, histone modification, and RNA processing functions. These results suggest that the prenatal maternal blood transcriptome is a sensitive indicator of gestational one‐carbon metabolite status and changes relevant to children's later neurodevelopmental outcomes. Lay Summary Pregnancy is a time when maternal nutrition could interact with genetic risk for autism spectrum disorder. Blood samples collected during pregnancy from mothers who had a prior child with autism were examined for gene expression and nutrient metabolites, then compared to the diagnosis of the child at age three. Expression differences in gene pathways related to the immune system and gene regulation were observed for pregnancies of children with autism and non‐typical neurodevelopment and were associated with maternal nutrients.

Placental methylome reveals a 22q13.33 brain regulatory gene locus associated with autism

“…The Markers of Autism Risk in Babies -Learning Early Signs (MARBLES) study [77] recruited mothers with at least one child that had been diagnosed with ASD and who were pregnant or planning another pregnancy in Northern California, primarily through lists provided by the California Department of Development Services [21,[77][78][79]. The following criteria were required for MARBLES study's enrollment: the prospective child has at least one first or second degree relative diagnosed with ASD; the mother is at least 18 years old; the mother is pregnant or planning for a pregnancy; the mother speaks, reads, and understands English proficiently enough in order to complete the protocol; and the mother lives within a 2.5-h drive distance of Davis/Sacramento region.…”

Early Life Nutrition and Mental Health: The Role of DNA Methylation

“…Another human study investigated the effects of one-carbon micronutrient deficiency, such as folate, betaine and 5′-methyltetrahydrofolate (5Mthf), in prenatal maternal blood on neurodevelopment and increased risk of autism in children after birth. Gene expression analysis of maternal blood revealed changes in the expression of immune, apoptotic, epigenetic and development-related genes, suggesting an association between the deficiency in one-carbon nutrients and neurodevelopmental delay and the development of autism in children [ 97 ]. Another neurodevelopmental disorder, Rett Syndrome, is considered one of the main causes of mental retardation in girls and is due to a deficiency in part of the epigenetic machinery, such as the methyl–CpG binding protein 2 (MeCP2) [ 98 ].…”

Delineation of Functional Changes and Associated Cortical Transcriptomic Profiles for Autism Spectrum Disorders

“…Among these hub genes, the genes of CAMK2 and GRIA1 which play key roles in the signal transmission between neurons have been widely reported in ASD. The CAMK2G is involved in formation and plasticity maintenance of neuronal synapses, and abnormal expression leads to impaired neuron maturation (Proietti Onori et al, 2018;Zhu et al, 2021). The GRIA1 is involved in regulation of inhibitory neurotransmitter receptors (glutamate receptor ANAR) (Montanari et al, 2022), and the decreased synaptic transmission activity of inhibitory signals can lead to the imbalance of neuronal excitation/inhibition (Hwang et al, 2022).…”