The Peculiarities Of Hereditary Schizophrenia

Introduction

Schizophrenia has existed for hundreds of years but was more recognised as its own mental disease in 1887 by German psychiatrist Emil Kraepelin who called it ‘dementia praecox’, meaning dementia in early life, this was changed to schizophrenia in 1910 by Swiss psychiatrist Paul Eugen Bleuler, where in Greek ‘schizo’ means split and ‘phren’ means mind. (Burton, 2012)

The disease is a progressive neurodevelopment disorder which affects 1% of the world’s population, of those affected 80% has a hereditary form (Vrijenhoek, et al., 2008), the remaining sufferers have environmental schizophrenia; not all people who have a hereditary form suffer symptoms and environmental stimulus can cause symptoms to appear in both hereditary and environmental schizophrenia.

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This graded unit will focus on the causes of hereditary schizophrenia, looking at the human genome and brain and how alterations to specific areas can cause the disease, with a brief look at the areas that may have an effect on the dopaminergic and glutamatergic regions, and how these can have an effect on the symptoms of the disease.

There is conflicting data as to which chromosomes are responsible for schizophrenia; several different chromosomes have been associated with the disease, the most researched is chromosome 22, deletions on this chromosome appear frequently in genome analysis in sufferers. Chromosomes 6 and 10 have also been associated with schizophrenia.

SNPs have been analysed for their association with the disease, although in general SNPs associated with disease are non-coding (Law, et al., 2016) they could possibly have an effect on gene splicing and expression which could in turn effect protein function and distribution (Law, et al., 2016).

Just as important as SNPs in the human genome are CNVs located on chromosomes, these are inherited from parents and the more disease associated CNVs an individual has the more severe the disease is likely to be. The same techniques used to identify SNPs are used for CNVs, the copy number calculations are estimated as de novo CNVs are also included as these cannot be identified and separated during the process; alterations to CNVs can disrupt genes and functional sequences in the chromosomal segment where they are located.

The symptoms of schizophrenia may not appear until adolescence or early adulthood, the onset can depend on previous trauma or substance abuse as well as the mutations inherited. Many factors have been associated with the cause of the symptoms, including prenatal care and viral infection; depending on environmental factors, such as upbringing and abuse coupled with the inheritance of mutations, the severity of the symptoms can change drastically between sufferers.

Inheritance of schizophrenia

The causes of schizophrenia has been researched for decades, with the progression of research techniques available it has been possible to establish that schizophrenia is a hereditary disease and the origin of the disease can be located in the sufferer’s brain and DNA.

[image: ]Structural differences in the brain of people suffering schizophrenia have been recognised with the use of MRI and CT scans, the results identified a reduced cortical thickness and a reduction in grey matter, as well as enlarged ventricles and decreased neurites and dendritic spines. The dorsolateral prefrontal cortex, superior temporal gyrus and hippocampus all had a reduction in the size of their pyramidal cells and displayed fewer dendritic spines and processes (Sontheimer, 2015). It has been suggested that changes in the brain structure begin prenatally, thisBlog, B., 2016. The Psychosis of Schizophrenia.

While studying the brain the chemical F-Dopa was used and with the use of CT and PET scans pre-synaptic concentrations of dopamine were observed, an issue with the dopaminergic neurons was recognised, this produced reduced synaptic activity and dendritic connectivity between neurons (Sontheimer, 2015). The reduction in dopaminergic neurons results in negative symptoms suffered including lack of energy and anhedonia (Sontheimer, 2015), the use of drugs such as amphetamines enhances dopamine production which can cause the positive symptoms of schizophrenia, such as hallucinations and delusions. Most antipsychotic drugs inhibit the D2 receptor to control symptoms, but this can have adverse effects and cause Parkinson’s disease like symptoms. Another drug which causes schizophrenia symptoms when abused is phencyclidine which inhibits NMDA receptors producing symptoms of psychosis (Bear, et al., 2007) this is an environmental cause of schizophrenia which can affect anyone.

The glutamatergic and GABAergic synapses are also affected in schizophrenia sufferers; these are measured suing CT scans. A reduction in glutamic acid decarboxylase affects the synthesis of GABA and decreased sub-units of alph-1 in GABA cause a 50% decrease in GABAergic synapses (Sontheimer, 2015). The glutamatergic input has an effect in the dendritic spines and the number of synapses is directly affected by genetic mutations, changes in the spines include reduction in size through childhood and adolescence and genetic mutations can alter how these degenerate.

The glutamatergic and GABAergic synapse deficiencies can be linked to a deletion of around 3 million base pairs on chromosome 22, which on a whole has 51 million base pairs; making up almost 2% of a person’s DNA and the second smallest chromosome. A deletion on chromosome 22q11.2 containing 30 to 40 genes and has many medical implications with one of these being schizophrenia (Medicine, 2019).

Two genes, specifically, that were identified as being deleted from chromosome 22 are microRNA’s, more precisely DGC8, consisting of on average 25 nucleotides it produces non coding RNA for mRNA’s needed to regulate protein expression and regulate dendrite and spine development; and miR185 which regulates the endoplasmic reticulum and the modulation of calcium for synaptic plasticity, it also effects dendrite branches by destabilizing the actin cytoskeleton, this gene is also responsible for the regulation of dendritic and spine development (Sontheimer, 2015), this would explain why decreased neurites and dendritic spines have been identified in areas of the brain, specifically the dendritic spines in those who have had negative environmental factors during early stages of development and have cognitive impairments (Bear, et al., 2007).

During studies identification of four genes the code for proteins have been deleted which have an effect on symptoms of schizophrenia, these genes are; DISC1, which encodes for scaffold proteins used in neurite outgrowth and cortical development (Database, n.d.); COMT, which catalyses transfer of neurotransmitters dopamine, epinephrine and norepinephrine as well as others (Database, n.d.); NRG1, this is responsible to membrane glycoproteins which aid in cell to cell signalling, the proteins also create isoforms by promotor usage and splicing creating a variety named type I to VI (Database, n.d.); and ERBB4 which is one of four tyrosine kinase receptors and has cell surface receptors for NRG1, as well as other genes (Database, n.d.). The latter two are responsible for orderly development in the cortex and expressing GABAergic interneurons which cause the reduced grey matter in the brain (Sontheimer, 2015).

There are several studies relating to the chromosomes affected in schizophrenia, although all of these studies have conflicting data as to the main chromosome or chromosomes affected and the results are only suggestive. Chromosome 22 is one of many linked to the disease, but many others have shown a significance which could result in symptoms relating to schizophrenia among other [image: ]diseases. Most studies have followed the same methods over a variety of ethnicities and some have been successful while others have produced poor results.

One such study was a genome wide autosomal screen carried out on 71 families, 305 individuals, in Munich, Germany and the results of the study highlight the mutations found on McDonald-McGinn, D. M. et al., 2015. Nature Reviews: Disease Primers.

The analysis of chromosomes in the first study had focussed on sib-pair analysis and transmission disequilibrium, of the 71 families analysed there were 86 independent sib-pairs. The results vary depending on LOD scores and model free methods (S G Schwab, 2000). For the sib-pair analysis nuclear families were used, where 2 siblings are affected but the parents don’t have the disease; both parents and at least one child has the disease; and first and second degree relatives have the disease. The results of the analysis showed 462 polymorphic markers (S G Schwab, 2000). The second study compared established neurodevelopment disorder CNV risk loci to healthy controls as well as schizophrenia sufferers and other mental illnesses, the results of the second study found that 58 of the neurodevelopment disorders had risk CNV’s at 23 of the 63 risk loci in the comparison to the healthy controls (Wolfe, et al., 2019).

For the results to be linked genetically and to prove that the disease is inherited the family and medical history was required for each individual in both studies, each person was reviewed by a psychiatrist who was completely independent from the study and had no knowledge of the person or their relationship to any other people being reviewed. The use of research diagnostic criteria gave an estimated diagnosis of each individual in the first study. Of those involved in the first study 138 were affected by schizophrenia predominantly, while other mental illnesses were recorded for the remaining individuals, such as depression or bipolar disorder (S G Schwab, 2000).

During the first study, while looking for the markers present on the chromosomes responsible, the distance was also recorded. It was noted that the distances were much larger in sufferers than non-sufferers, possibly due to genetic mutations passed from previous generations. The average distance between markers is typically 10cM, however in the study the distance between markers on chromosome 6q5.2 was 22cM and on chromosome 22q13.3 there was 20cM recorded, while the remaining markers all had between 1 and 3cM (S G Schwab, 2000). The study found mutations on ten different chromosomes; however, chromosome 6 showed high LOD scores and significant distances between markers and chromosomes 10 showed high LOD scores on specific markers and excess transmission from allele II, these findings are similar to those found in bipolar sufferers too (S G Schwab, 2000).

Irregularities on areas of DNA called SNPs have also been associated with schizophrenia. 90% of sequence variants are due to single base differences, and large chromosomal re-arrangements are detected by array comparative genomic hybridization which analyse the fluorescence signal intensities of clones (Wang, et al., 2008). SNPs are found in coding and regulatory regions affecting functional differences but most SNPs don’t affect gene function (Collins, et al., 1998); however disease associated SNPs are located in non-coding regions (Law, et al., 2016). There are several techniques used to locate SNP and NP markers, Illumina which measures two signal intensities of each SNP which produces the Log R ratio (LRR) and B allele frequency (BAF). The signal intensities then undergo a normalization procedure which determines the X and Y values, this then produces the normalised signal intensity for A and B alleles (Wang, et al., 2008), another technique used is Affymetrix SNP arrays which have genome wide 5.0 and 6.0 arrays and contains equal numbers of SNP and NP markers, similar to the Illumina procedure the LRR and BAF are analysed as well as allele specific intensities for three genotypes (Wang, et al., 2008). SNP mutations can naturally occur in the body, these are usually included in the probability, and this is why while analysing DNA for mutations it is best to use DNA from a known sufferer to identifying gene sequences responsible and comparing with control DNA from individuals who do not have the disease.

Some studies have concentrated on specific SNPs associated with schizophrenia, one study identified two specific SNPs associated with schizophrenia, these are SNP8NRG221132 and SNP8NRG243177, and these have an effect on binding sites for three transcription factors, myelin transcription factor-1, serum response factor and high mobility group box protein-1 (Law, et al., 2016). Another is NRG1, locating risk haplotypes focussed on the study of the 5’ upstream region, here is where an effect on mRNA abundance of NRG1 type I – IV can be located, this was analysed in the hippocampus post mortem (Law, et al., 2016). Sufferers of schizophrenia had an increase in NRG1 type I of 34% and another SNP with a risk haplotype had a block on 22kb, this SNP caused issues with mRNA expression in type IV, this was present in both sufferers and known schizophrenic controls used (Law, et al., 2016).

There have been several links between schizophrenia and NRG1 one of which involves the deletion on chromosome 22; this contributes to the reduced grey matter in the brain (Sontheimer, 2015). NRG1 has pleotropic roles in neurodevelopment and plasticity, consisting on 1.2 Mb is has many structurally and functionally distinct isoforms (Law, et al., 2016). Studies focus on the core haplotype or overlapping markers in the 5’ regions, however the impact of these abnormalities is unclear as these are non-coding regions. One possibility is that the mutations alter expression which affects protein distribution and function. There is evidence that increasing NRG1 type I can affect the mRNA in the prefrontal cortex of individuals with schizophrenia, altered gene splicing and expression has also been observed particularly as a polymorphic variation in brain diseases (Law, et al., 2016).

Analysis in genome studies is most often based on family history and DNA and knowing the copy numbers responsible makes locating them easier, by using quantitive PCR the total copy numbers from family DNA can be calculated (Wang, et al., 2008). During studies there are two levels of dependency to consider the first being Markov chain dependency which identifies the probabilities of hidden copy numbers and the second is mendelian inheritance where genes show segregation of two alleles in gametes during meiosis (Wang, et al., 2008).

CNVs are also located on chromosomes and are just as important as SNPs in genomic diversity, 40 CNVs have been linked to disease with the most popular CNVs being TNRs (Clancy, 2008). CNVs have been identified as inherited from parents and the greater the number of inherited CNVs relating to disease the more severe symptoms can be (Clancy, 2008). CNVs are part of the diploid genome and are chromosome specific, they can exist in any two of the homologous chromosomes and so can be deleted or duplicated in one or the other (Wang, et al., 2008). Studies on CNVs have identified expansion and contraction of gene sequences, although expansion is less likely, except in TNRs which expand with age (Clancy, 2008). With the use of family DNA it is possible to locate CNVs associated with schizophrenia, Affymetrix and Illumina techniques are used to locate these as with SNPs. The total copy numbers can be detected by using PCR to duplicate DNA for better analysis. The copy number in the diploid genome can only be estimated as de novo CNVs, which are not inherited, are also included in calculations and so complicate the analysis (Wang, et al., 2008).

The chromosomal segment occupied by CNVs contains 1kb of functional sequences, where a deletion or duplication exists; this can disrupt the gene and delete alleles (Wang, et al., 2008).CNVs account for anywhere between 6% and 19% of chromosomes and can be found all over the human genome, any mutation to CNVs can change the physical arrangements in chromosomes (Clancy, 2008). Signal intensities in the human genome are analysed in large arrangements using array comparative genomic hybridization and whole genome oligonucleotide arrays, these methods do not require the use of SNPs for analysis (Wang, et al., 2008).

Environmental triggers of schizophrenia

Many areas of the human genome can be mutated to have adverse effects on the body, some mutations can exist without being known, and symptoms can develop as an individual ages or can be onset by environmental factors. Trauma through childhood and adolescence, known as the prodromal phase, as well as substance abuse can contribute to symptoms of schizophrenia and a psychotic attack where violent behaviour is displayed (Sontheimer, 2015). Children with schizophrenia can express symptoms of a different nature such as development delays and cognitive problems (Howes, et al., 2004). Social stresses can cause symptoms of schizophrenia especially in adolescence and early adulthood where there are multiple risk factors (Howes, et al., 2004). Mutations which are inherited are not uncommon to every person but when there is a mixture of mutations and environmental factors involved this can cause symptoms of psychosis.

While analysing the brain in some sufferers there was a decrease in the left hippocampal volume and increased ventricular volume, this was more prominent in people who had suffered obstetric complications such as being small for gestational age. Other affecters of the brain analysed were maternal substance abuse and prenatal infection (Howes, et al., 2004). Studies have been carried out on infants born in winter months as it is believed that this could have an effect on development due to prenatal viral infections, compared to infants born in summer months where mothers were less likely to have viral issues (Sontheimer, 2015). Social stresses can also impact symptoms as these can cause an increase in dopamine which can induce symptoms of psychosis, childhood trauma and ethnicity have also been associated with symptoms of schizophrenia. Studies have found that people who are raised in urban areas in minority populations are at a higher risk of developing schizophrenia; this can be due to social isolation, compared to people raised in rural areas where the risks are much lower (Howes, et al., 2004).

Substance abuse has a serious effect on the symptoms of schizophrenia, particularly cannabis, amphetamines and cocaine; these can all increase the risk of psychosis (Howes, et al., 2004). PCP can induce psychosis, whether they have genetic mutations linked to schizophrenia or not. Cannabis is the most common cause of symptoms, most users self-medicate with the drug and when abused in adolescence increases the risk of psychosis by four times. Amphetamines are dopamine releasing drugs that can lead to severe symptoms of psychosis and sufferers who are sensitive to dopamine are more likely to incur issues with the regulation of dopamine (Howes, et al., 2004).

Comparing a sufferer of schizophrenia to an unaffected person while using amphetamines resulted in psychosis in the schizophrenia sufferer only, depending on the amount of drug abused the severity and length of the psychosis changed; if the drug was used more frequently for longer periods then the psychosis was more permanent than those who only used on an irregular basis. The more vulnerable a person is to schizophrenia due to inheritance of mutated genes then more vulnerable they are to develop psychosis through misuse of drugs (Howes, et al., 2004).

Childhood traumas such as sexual, physical or emotional abuse increase the risks of developing schizophrenia, with 11% of sexual abuse victims and 26% of physical abuse victims more likely to have a psychotic disorder. The trauma affects the children as they progress through life and can lead to depression, personality disorders and PTSD (Morgan & Fisher, 2007), all of which place the person at an even higher risk of developing a psychosis. Children who suffered sexual abuse were more likely to develop depression and border line personality disorder as an adult and those who suffered physical abuse were more likely to have an antisocial personality disorder. People, who had suffered sexual abuse at any age, not only childhood, were fifteen more times likely to have a psychiatric disorder like schizophrenia (Morgan & Fisher, 2007). Hallucinations were observed in people who had suffered varied childhood trauma and the age of the victim, duration, nature and severity of abuse all affected the outcome of psychosis and severity of symptoms (Morgan & Fisher, 2007). All studies carried out on childhood trauma have been conflicting, some studies have been more thorough while others have not, many have not included extensive questioning to those who have suffered the abuse to compare results to other cases similar, however there does appear to be a link between childhood trauma and developing schizophrenia as well as other psychiatric disorders, with or without inheritance of mutated genes.

Summary

Hereditary schizophrenia is a very complex neurodevelopmental disease, starting during the very early stages of foetal development, it may not be possible to prevent, only treat symptoms. Mutations in the human genome are passed through generations, while some form on their own, a mixture of mutations on specific chromosomes, SNPs or CNVs can cause disease and can make a person high risk to symptoms. With schizophrenia those mutations exist all through the human genome and the brain, through development and exposure to environmental factors schizophrenia symptoms appear with severity dependant on all factors of the disease.

Studying this topic has led to the conclusion that a specific gene may be responsible for more than one issue relating to schizophrenia, that gene is NRG1. Through research for this graded unit this gene has appeared in several studies and putting all that information together it appears that the gene may be responsible for several factors in the disease. When analysing SNPs it was found that NRG1 was responsible for an abundance of mRNA in type I to V, where an increase in type I was identified in sufferers as well as type IV which affects mRNA expression. When analysing research on chromosome 22 deletions NRG1, again, was associated with the disease, in its contribution to reducing grey matter in the brain. With the genes ability to create isoforms for promotor usage and splicing DNA, there could be a connection between this protein and foetal development.

Chromosome 22 is highly associated with schizophrenia, during research it was found in both studies concerning affected chromosomes, although other chromosomes were detected in both studies, neither were concordant. Chromosome 22 appears to be the main focus of study in association to the disease. With the deletion of two genes on the chromosome the dendritic spines in the brain are affected, this is seen in brain scan along with other abnormalities in sufferers of the disease. It has been suggested that this could be caused by viral infection during foetal development possibly passed maternally. The development of dendritic spines has also been associated with a dysfunction in the glutamatergic and dopaminergic synapses, these cause a degradation of the neurites, dendritic spines and the enlargement of ventricles. The reductions of dendritic spines reduced the synaptic activity and connections between dendritic neurons causing negative symptoms.

Following mendelian inheritance with the segregation in gametes during meiosis, the mutation from one or both parents is passed onto the foetus. Through development these mutations shape the brain and the possibility of effects occur due to exposure to viruses.

Throughout childhood development delays and cognitive problems present themselves as the first symptoms, however not all children with these symptoms will develop schizophrenia. During childhood and adolescence exposure to environmental factors such as abuse in childhood and social stresses can affect the sufferers. Drug abuse enhances the risk of developing severe symptoms of psychosis due to the release of dopamine; this can encourage positive symptoms of the disease.

During adulthood the control of the disease is most effective, using anti-psychotic drugs to inhibit dopamine receptors and avoiding drugs that stimulate the production of dopamine.

Schizophrenia is a progressive neurodevelopment disorder which affects 1% of the world’s population, with 80% of sufferers having a hereditary form. Genetic mutations and environmental factors contribute to the severity of the disease and with the use of anti-psychotic drugs; avoidance of drug abuse and social stresses the symptoms can be controlled. Using family medical history and DNA to identify genetic abnormalities research continues to find the main cause of schizophrenia and understand better how and when the disease is inherited.

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