Heredity, epigenetic and
Relationship between environmental factors and autism
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Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder whose core symptoms include social deficits and restrictive/repetitive behaviors. In the 1960s, scientists discovered that ASD may be the result of an interaction of genetic and environmental factors. At present, the prevalence of ASD is increasing year by year, and the symptoms often accompany the patient for a lifetime, bringing a serious burden to the patient's family and society. In this case, looking for genetic changes and biomarkers associated with ASD becomes the basis for early diagnosis and intervention in ASD.
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Genetic and epigenetic factors
GENETIC AND EPIGENETIC FACTORS
A study of twins reported in the 1970s found that genetic factors were associated with the onset and development of autism. The heritability of traits can be estimated by comparing phenotypic consistency between identical twins (MZ) with 100% genetic similarity and heterozygotic twins (DZ) with approximately 50% genetic similarity. The greater the difference in phenotypic consistency, the higher the contribution of heritability and genetic factors. Identical twins (60-90%) have autism at the same time compared to fraternal twins (5-40%), proving that genetic factors play an important role, but the comorbidity rate of identical twins does not reach 100%, meaning that genetics or other factors together influence the appearance of ASD.
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Their role in the pathogenesis of autism
ROLE IN PATHOGENESIS
In terms of genetic variation, there is growing evidence that different variants of copy number play an important role in human neuropsychiatric diseases. New CNVs in patients with ASD are 3-5 times higher than other family members and healthy controls. CNVs can influence gene expression and thus participate in the onset and development of diseases through a variety of mechanisms, including gene disruption, location effects, gene fusion, and recessive alleles. CNVs screening has been shown to be the preferred method for identifying GENES associated with ASD susceptibility. Although CNVs associated with the disease are often unique and occur less frequently in the population, the study found that 8–21% of PATIENTS with ASD had CNVs, which are likely to be associated with severe clinical symptoms.
While most studies aimed at understanding the etiology of ASD have focused on the genetic component, it has been found that genetic mutations occur only in a small number of patients. This phenomenon is known as the "problem of missing heritability," and it is a common problem in the most complex genetic diseases.
Many hypotheses have been proposed to explain phenomena that cannot detect genetic problems, such as mutants with unknown characteristics, genotype/genotype interactions, incomplete penetration, epigenetic factors, and genotype/environmental interactions.
Candidate for gene
Case-control studies of human and animal models have identified more than 800 genes associated with autism. The most affected genes in ASD encode proteins involved in chromatin remodeling and transcriptional regulation, cell proliferation, and most synaptic structures and functions.
Epigenetic factors
DNA methylation: Studies of autistic patients and healthy controls, as well as lymphocyte lines and whole blood DNA of identical twins, found that there were different methylation regions between autistic patients and controls, as well as identical twins. Another study of the placenta and placenta of children later diagnosed with ASD found that there were more than 400 distinct methylated regions between the two groups, including gene promoters involved in neuronal development.
miRNA: Some studies have found that the expression profile of MiRNA in saliva, blood, and brain tissue in patients with ASD is imbalanced. Downregulation of miR-6126 was detected in peripheral blood samples from adult PATIENTS with ASD. The predictive targets of miRNAs belong to neuronal and oxytocin pathways. Similarly, it has been found that there is a significant decrease in the trend of 6 mirnas (Mir-19a-3p, miR-361-5p, miR-3613-3p, miR-150-5p, miR-126-3p and miR-499a-5p) in serum samples of children with ASD and their unaffected family members compared with healthy controls. This result has been validated in blood, hypothalamus, and sperm in mouse models of ASD.
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environmental factors
ENVIRONMENTAL FACTORS
Studies have found that up to 40-50% of differences in ASD risk can be determined by environmental factors such as drugs, toxic exposure, parental age, nutrition, production environment, etc.
The age of parents is one of the most defining environmental risk factors for autism spectrum disorder. Much evidence suggests that older fathers are associated with the development of bipolar disorder, schizophrenia, hyperactivity, and autism. A meta-analysis of 27 studies on the relationship between parental age and autism showed that if the age of mother and father increased by 10 years, the risk of autism in offspring may increase by 20%.
Perinatal risk factors are also one of the most studied risk factors for ASD and one of the most difficult to identify and predict in advance. Two meta-analyses of 60 perinatal factors showed a statistically significant correlation between ASD risk and cord complications, birth or trauma, multiple births, maternal bleeding, low birth weight, neonatal anemia, genital malformations, ABO or R blood group incompatibility, and hyperbilirubinemia.
Vitamin and trace element deficiencies increase the risk of developing autism. A Swedish study found that maternal vitamin D deficiency was associated with the risk of autism in offspring, and an imbalance in vitamin levels was also found in children with autism. In addition, the literature reports that vitamin supplementation can improve core symptoms in patients with ASD.
Summary above
Given the complexity of the etiology of autism and the increase in cases worldwide, there is an urgent need to find effective diagnostic methods, study as many risk factors as possible, and prevent the occurrence of the disease as much as possible.
In fact, as a multi-causal disease, risk factors are not only genetic factors, but also epigenetic factors and environmental factors, and a large number of studies in recent years have proved to be related to enterobacterial disorders, and also involve metabolic abnormalities, immune problems and so on. At the same time, genetic/environmental interactions and interactions between risk factors cannot be ignored.
参考文献：Masini, E., Loi, E., Vega-Benedetti, A. F., Carta, M., Doneddu, G., Fadda, R., & Zavattari, P. (2020). An Overview of the Main Genetic, Epigenetic and Environmental Factors Involved in Autism Spectrum Disorder Focusing on Synaptic Activity. International journal of molecular sciences, 21(21), 8290.