User:RG2022/Epigenetics of schizophrenia

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PEER REVIEW: Overall good info, but maybe adding some more information in general would be better. Some background on what epigenetics is and what epigenetic markings do would also fit this well.

Heritability[edit]
Studies have shown that epigenetic changes can be passed on to future generations through meiosis and mitosis. These findings suggest that environmental factors that the parents face can possibly affect how the child's genetic code is regulated. Research findings have shown this to be true for patients with schizophrenia as well. In rats, the transmission of maternal behavior and even stress responses can be attributed to how certain genes in the hippocampus of the mother are methylated. Another study has shown that the methylation of the BDNF gene, which can be affected by early life stress and abuse, is also transmittable to future generations. Epigenetics of schizophrenia

Schizophrenia (SZ) is regulated by both environmental and genetic factors. It has been calculated that 80% of the heritability of SZ comes from genetics, 30% from single nucleotide polymorphisms, and another 30% from large copy number variants. However, it is unknown the extent to which interactions between environmental and genetics factors contribute to the development of schizophrenia. In some circumstances, it has been shown that environmental factors can increase the risk of SZ when combined with a family history of psychosis.

Genetics[edit]
Several genes have been identified as important in the study of schizophrenia, but there are a few that have special roles when studying the epigenetic modifications of the disease.


 * GAD1- GAD1 codes for the protein GAD67, an enzyme that catalyzes the formation of GABA from glutamate. Individuals with schizophrenia have shown a decrease in GAD67 levels and this deficit is thought to lead to working memory problems, among other impairments.
 * RELN- RELN codes for reelin, an extracellular protein that is necessary for formation of memories and learning through plasticity. Reelin is thought to regulate nearby glutamate producing neurons.

Both proteins are created by GABAergic neurons. Several studies have demonstrated that levels of both reelin and GAD67 are downregulated in patients with schizophrenia and animal models.


 * BDNF - Brain-derived neurotrophic factor, BDNF, is another important gene in the study of schizophrenia genetics. BDNF plays a crucial role in cognition, learning, memory formation, and vulnerability to social and life experiences. Epigenetics of schizophrenia

Genome-wide association studies (GWAS) have further confirmed the presence of many genes for the regulation of schizophrenia. Chromosomal regions containing a large number of CNVs are reported to lead to increased susceptibility to SZ. Linkage studies have proved to be unsuccessful due to the interaction of several different genes that are all involved in the development of SZ. There are also no specific SNPs majorly involved in the development of schizophrenia, however groups of SNPs could account for 30% of the genetic susceptibility for developing schizophrenia. In contrasts, rare CNVs have been shown to lead to a greater genetic risk for SZ, however, these CNVs have also been found in control subjects as well as implicated in other mental disorders such as autism. In the cases of the CNVs shown to be involved in SZ development, de novo rather than inherited CNVs are involved, and the de novo mutations may not be able to cause schizophrenia single-handedly without interaction with other genetic factors.

Environmental risks and causes[edit]
While there haven't been many studies linking environmental factors to schizophrenia-related epigenetics mechanisms at this point in the field, a few studies have shown interesting results. Advanced paternal age is one of the risk factors for schizophrenia, according to recent research. This is through mutagenesis, which cause further spontaneous changes, or through genomic imprinting. As the parent ages, more and more errors may occur in the epigenetic process. There is also evidence of the association between the inhalation of benzene through the burning of wood and schizophrenic development. This might occur through epigenetic changes. Methamphetamine has also been linked to schizophrenia or similar psychotic symptoms. A recent study found that methamphetamine users had altered DNMT1 levels, similar to how patients with schizophrenia have shown abnormal levels of DNMT1 in GABAergic neurons.

One of the most interesting findings relating an environmental factor with schizophrenic epigenetic mechanisms is exposure to nicotine. It has been widely reported that 80% of patients with schizophrenia use some form of tobacco. Furthermore, smoking appeared to increase cognition in individuals with schizophrenia. However, it was only a recent study Satta et al.that showed that nicotine leads to decreased levels of DNMT1 in GABAergic mouse neurons, a molecule which adds methyl groups to DNA. This led to increased expression of GAD67. Epigenetics of schizophrenia

Prenatal exposures can lead to an increased likelihood of schizophrenia. Viral infections, while unable to cross the placenta, can impact the fetus through the proinflammatory cytokines developed by the mother as a part of the immune response against the virus. Interleukin-8 has been shown to increase the risk of SZ when the fetus is exposed to it in the womb by causing structural changes in the CNS. Some inflammatory cytokines such as IL-6 can cross the placental barrier early in the pregnancy but not later, indicating that the time of the infection is important in SZ risk assessment. Cytokines cause microglia activation in the developing fetus, which can cause toxicity affecting neurodevelopment.

Deficiencies in certain nutrients including choline, folate and vitamin B12 required for the creation S-adenosylmethionine (SAM) are also linked with increasing the epigenetic factors associated with increased SZ risk.