epigenetics of schizophrenia epigenetics of schizophrenia the epigenetics of schizophrenia is the study of how the inherited epigenetic changes are regulated and modified by the environment and external factors, and how these changes shape and influence the onset and development of, and vulnerability to, schizophrenia. epigenetics also studies how these genetic modifications can be passed on to future generations. schizophrenia is a debilitating and often misunderstood disorder that affects up to 1% of the world's population. while schizophrenia is a heavily studied disorder, it has remained largely impervious to scientific understanding, so epigenetics offers a new avenue for research, understanding, and treatment. background history historically, schizophrenia has been studied and examined through different paradigms, or schools of thought. in the late 1870s, emil kraepelin started the idea of studying it as an illness. another paradigm, introduced by zubin and spring in 1977, was the stress-vulnerability model where the individual has unique characteristics that give him or her strengths or vulnerabilities to deal with stress, a predisposition for schizophrenia. more recently, with the decoding of the human genome, there had been a focus on identifying specific genes to study the disease. however, the genetics paradigm faced problems with inconsistent, inconclusive, and variable results. the most recent school of thought is studying schizophrenia through epigenetics. a visualization of the stress-vulnerability model, also known as the diathesis-stress model the idea of epigenetics has been described as far back as 1942, when conrad waddington described it as how the environment regulated genetics. as the field and available technology has progressed, the term has come to also refer to the molecular mechanisms of regulation. the concept that these epigenetic changes can be passed on to future generations has progressively become more accepted. while epigenetics is a relatively new field of study, specific applications and focus on mental disorders like schizophrenia is an even more recent area of research. symptoms the core symptoms of schizophrenia can be classified into three broad categories. these symptoms are often used to build and study animal models of schizophrenia in the field of epigenetics. positive symptoms are considered limbic system aberrations, while negative and cognitive symptoms are thought of as frontal lobe abnormalities. positive symptoms: the limbic system and associated structures of the brain, where abnormalities lead to positive symptoms of schizophrenia. hallucination delusions and paranoia thought disorders negative symptoms: apathy poverty of speech flat or blunted emotions cognitive dysfunctions: impaired working memory disorganized thoughts cognitive impairments heritability heritability represents the percentage in variability in a trait that comes from genetic differences. there is a great deal of evidence to show that schizophrenia is a heritable disease. it has been calculated that the heritability of schizophrenia is around 80%, and within that heritability 30% of the variability comes from single nucleotide polymorphisms and another 30% from large copy number variants (cnvs). one key piece of evidence is a twin study that showed that the likelihood of developing the disease is 53% for one member of monozygotic twins (twins with same genetic code), compared to the 15% for dizygotic twins, who don't share the exact dna. it has also been shown that having direct family members that are diagnosed with schizophrenia increases the rate of developing schizophrenia by 9 times. another study investigated the rates of schizophrenia of adoptees: adoptees with a genetic history of schizophrenia that were adopted by non-schizophrenic parents were seen to be diagnosed with schizophrenia at higher rates than adoptees without a biological history of schizophrenia but raised with adoptive parents diagnosed with schizophrenia. however, the extent to which interactions between environmental and genetic factors contribute to the development of schizophrenia is uncertain. others question the evidence of heritability due to different definitions of schizophrenia and the similar environment for both twins. that said, the fact that even monozygotic twins don't share a 100% concordance rate suggests environmental factors play a role in the vulnerability and development of the disorder. maternal immune responses are involved in schizophrenia development. a 2019 study found that, in mice models, maternal immune activation may be involved in the regulation of the arx gene expression that contributes to the gaba dysfunction commonly implicated in schizophrenia. most maternal effects involved in schizophrenia development have to do with immune system activation and associated cytokine and neurogenesis mechanisms rather than genetic changes. paternal genetic effects are seen to be involved in the rate of development of schizophrenia. a 2021 study showed that advanced paternal age was associated with higher schizophrenia risk. in the study, the paternal ages were grouped into 5-year increments, and it was seen that as the increments increased, so did the risk of developing schizophrenia. it is hypothesized that advanced paternal age increases schizophrenia risk because fathers pass down three to four times more de novo mutations than do mothers. it is estimated that 2 new de novo mutations are created a year, resulting in fathers with an advanced age passing down more mutations to their offspring, which may explain the increased rates of schizophrenia. there are various environmental factors that have been suggested, including the use of marijuana, complications during pregnancy, socioeconomic status and environment, and maternal malnutrition. in some circumstances, it has been shown that environmental factors can increase the risk of schizophrenia when combined with a family history of psychosis. as the field of epigenetics advances, these and other external risk factors are likely to be considered in epidemiological studies. genes associated with schizophrenia among the many genes known to be associated with schizophrenia, a few have been identified as particularly important when studying the epigenetic phenomena underlying 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 expressed 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. genome-wide association studies (gwas) have confirmed the presence of other genes thought to be involved in the regulation of schizophrenia. several genes that gwas have determined to be associated with schizophrenia include genes involved in neurodevelopment, including glutamatergic signaling, synaptic transmission, and the regulation of voltage-gated calcium channels. this includes the gad1 and reln pathways denoted above as well as bdnf. another important gene is the dopamine receptor 2 gene, which encodes a dopamine receptor (d2), a primary target of many of the antipsychotic drugs that are used to treat patients with schizophrenia. chromosomal regions containing a large number of cnvs are reported to lead to increased susceptibility to schizophrenia. copy number variants (cnvs) have also been reported to be associated with schizophrenia, particularly in chromosomal regions with large amounts of cnvs. a cnv located at the gene nrxn1, which encodes a neurexin protein involved in synaptic transmission, is thought to cause a loss-of-function mutation that is associated with the development of schizophrenia. loss-of-function mutations at the gene encoding histone h3 methyltransferase, an important enzyme for epigenetic histone modification, have also been implicated in gene-association studies for schizophrenia. histone modification is not the only epigenetic mechanism thought to be commonly associated with schizophrenia. analyzing schizophrenia-associated genes reveals that risk loci are commonly found near dna methylation quantitative trait loci (which affect cpg methylation), which have post-transcriptional modifications uniquely correlated to schizophrenia and produce splice variants with strong chromatin associations. dna methylation, post-transcriptional modification and splice variation, and chromatin modifications are all prominent epigenetic mechanisms, and their association with schizophrenia-risk-associated loci indicates that these mechanisms may play a significant role in the development of the disease. moving away from gwas, linkage studies have proved to be unsuccessful due to the interaction of several different genes that are all involved in the development of schizophrenia. there are also few specific snps majorly involved in the development of schizophrenia, however groups of snps could account for 30% of the genetic susceptibility for developing schizophrenia. research methods epigenetics can be studied and researched through various methods. one of the most common methods is looking at postmortem brain tissue of patients with schizophrenia and analyzing them for biomarkers. other common methods include tissue culture studies of neurons, genome-wide analysis of non-brain cells in living patients (see pbmc), and transgenic and schizophrenic animal models. other studies that are currently being done or that can be done in the future include longitudinal studies of patients, "at-risk" populations, and monozygotic twins, and studies that examine specific gene-environment interactions and epigenetic effects. epigenetic alterations epigenetics (translated as "above genetics") is the study of how genes are regulated through reversible and heritable molecular mechanisms. the epigenetic changes modify gene expression through either activation of the gene that codes for a certain protein, or repression of the gene. there are two main categories of modifications: the methylation of dna and modifications to histones. research findings have demonstrated that several examples of both of these changes are linked to schizophrenia and its symptoms. evidence of epigenetic regulation is still sparse, and just as genetic culprits for the disease remain nebulous, there is no definite answer to what epigenetic alterations should be expected in patients with schizophrenia. mechanisms of epigenetics in the cell dna methylation dna methylation is the covalent addition of a methyl group to a segment of the dna code. these -ch3 groups are added to cytosine residues by the dnmt (dna methytransferases) enzymes. the binding methyl group to promoter regions interferes with the binding of transcription factors and silences the gene by preventing the transcription of that code. dna methylation is one of the most well studied epigenetic mechanisms and there have been several findings linking it to schizophrenia. differential dna methylation has been identified in the schizophrenic epigenome across 4 different regions of the brain. hypermethylation of genes in neurotransmitter pathways (including gad1, reln, and the serotonin pathway) as well as hypomethylation of genes in other pathways (such as the dopaminergic pathway) have been observed in schizophrenic patients. a broad range of genomic methylation patterns have been observed in patients with schizophrenia, and although a definite explanation is not in place, there are enough consistent abnormalities to suspect that differential methylation may play a substantial role in the pathogenesis of schizophrenia. methylation of gabaergic genes it has been consistently shown in various studies that levels of reelin and gad67 are downregulated in the cortical and hippocampal tissue samples of individuals with schizophrenia. these proteins are used by gabaergic neurons, and abnormalities in their levels could result in some of the symptoms found in individuals with schizophrenia. the genes for these two proteins are found in areas of the genetic code that can be methylated (see cpg island). recent studies have demonstrated an epigenetic link between the levels of the proteins and schizophrenia. one study found that cortical neurons with lower levels of gad67 and reelin also showed increased levels of dnmt1, one of the enzymes that adds a methyl group. it has also been shown that a schizophrenic-type state can be induced in mice when they were chronically given l-methionine, a precursor necessary for dnmt activity. these and other findings provide a strong link between epigenetic changes and schizophrenia. methylation of bdnf dna methylation can also affect expression of bdnf (brain derived neurotrophic factor). the bdnf protein is important for cognition, learning, and even vulnerability to early life trauma. sun et al. showed that fear condition led to changes in dna methylation levels in bdnf promoter regions in hippocampal neurons. it was also shown that inhibiting dnmt activity led to change in levels of bdnf in the hippocampus. methylation of bdnf dna has also been shown to be affected by post-natal social experiences, stressful environment, and social interaction deprivation. furthermore, these stimuli have also been linked to increased anxiety, problems with cognition, etc. while a direct link between schizophrenia and bdnf levels hasn't been established, these findings