Genes That Contribute To Schizophrenia
Nevertheless, an important implication of multi-factorial polygenic models is that genetic heterogeneity at least partly accounts for phenotypic heterogeneity. In fact, such a state of affairs would be consistent with heterogeneous genetic aetiologies evident in a variety of complex disorders. Phenylketonuria , for example, is associated with up to 200 alleles of the phenylalanine hydroxylase gene, which produces varying degrees of mental illness in the absence of treatment . Similarly, Gaucher’s disease, a fatal neurological syndrome, can be produced by three different genotypes . The notion of genetic heterogeneity extends even further. While most cases of schizophrenia are accounted for best by polygenic models, some may indeed result from the effects of one or several genes of moderate to large effects. In some cases, for example, family transmission patterns are predicted about as well by oligogenic models as they are by multi-factorial polygenic ones .
In the light of the high heritability estimates for schizophrenia, the discovery of genes that cause the disorder has been eagerly anticipated since the 1980s, spurred in part by the development of polymorphic DNA markers that can detect multiple forms of genes in chromosomal locations .
Schizotaxia And Future Research
If our concept of schizotaxia is correct – the syndrome still requires validation – then the genetic liability to schizophrenia shows meaningful clinical manifestations that have several implications. First, schizotaxia may be a more specific expression of schizophrenia genes than is psychosis, which may be associated with additional and not entirely related pathophysiological manifestations. This may be particularly true if suggestions of neurodegeneration in psychosis are correct, and have distinct aetiological bases.
Second, the treatment of schizotaxia in non-psychotic relatives could serve to attenuate clinically meaningful symptoms . This course of action was tested in a pilot study of four relatives with schizotaxia . The criteria for schizotaxia included moderate deficits in at least two neuropsychological domains, including long-term verbal memory, attention and executive functions , and moderate levels of negative symptoms rated 3 or higher). Individuals who met these criteria and agreed to treatment received low doses of risperidone for 6 weeks. Side-effects were temporary and mainly mild. All four individuals showed marked improvements in attention, and mild to moderate reductions in negative symptoms. We stress that these results are preliminary, and do not advocate this treatment until larger, more controlled trials have determined the reliability and validity of our findings.
Literature Review Genetic Studies
The effect of dopamine on schizophrenia has recently begun to be heavily investigated in the scientific community. Dopamine receptors, specifically D2 appear to be a probable contributing factor to the classic symptoms of Schizophrenia. The receptor availability of dopamine was measured in patients at the standard level as well as after drug administration to reduce available dopamine in 36 subjects. 18 of these subjects were schizophrenic patients and the other 18 were matched controls.
The dopamine receptor availability in each subject was measured with single-photon computerized emission tomography and the drug administered to reduce dopamine concentration was ?±-methyl-para-tyrosine . Upon the first initial analysis, no significant difference in standard dopamine receptor availability was noted between the schizophrenic and control subjects. However, after a decrease in available dopamine, significant results arose .
Upon depletion of dopamine with ?±-MPT, there was a significant increase in receptor availability in both schizophrenic patients and control subjects. This is an intuitive explanation as a decrease in dopamine would trick the brain into believing it needs more receptors to reach its normal level of dopamine binding. However, the increase in dopamine receptor availability was significantly higher in patients with Schizophrenia compared to the control subjects after the drug treatment. This data is illustrated below .
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City Living And Amygdala Activation + Urban Birth Tunes Cingulate Activation During Social Stress Processing
Using functional magnetic resonance imaging , researchers found that living in a city was associated with increased amygdala activity, indicative of stress processing differences compared to those living in a rural environment.
It was the first to suggest that brain regions differ in vulnerability to living in a city as a risk factor across the lifespan.
Lederbogen F, Kirsch P, Haddad L, et al. City living and urban upbringing affect neural social stress processing in humans. Nature 2011 474:498-501.
Using fMRI, researchers found that being born and living in a city for the first years of life affected the perigenual anterior cingulate cortex , a key region for regulation of amygdala activity, negative affect and stress.
Lederbogen F, Kirsch P, Haddad L, et al. City living and urban upbringing affect neural social stress processing in humans. Nature 2011 474:498-501.
It appears that living in or spending early years of life in the city has a profound impact on both structure and function of parts of the brain associated with stress and emotion processing. It begs the question, however, of what specifically may cause such functional and structure abnormalities in the brains of those who experience early life in an urban environment?
Overlap With Other Disorders
Several studies have suggested a genetic overlap and possible genetic correlation between schizophrenia and other psychiatric disorders including autism spectrum disorder, attention deficit hyperactivity disorder, bipolar disorder, and major depressive disorder. One genome-wide association study analyzed single-nucleotide polymorphism data for the five disorders four gene areas overlapped with the five disorders, two of which regulate calcium balance in the brain.
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Pedigree Studies: Lod Score Methods
In pedigrees with multiple ill individuals, the LOD score method can be used to determine whether the distribution of DNA markers alleles within each pedigree predicts presence of disease. The LOD score is based on a mathematical model of the mode of inheritance . Our uncertainty of the precise mode of inheritance in complex genetic disorder such as schizophrenia introduce the possibility of mis-specifying the model, resulting in inappropriate linkage data.
Mutant Models Of G E Interactions In Schizophrenia
Interactions between genetic risk and environmental stressors at various stages of life appear important in the development of schizophrenia . Preclinical genetic models provide tools for assessing the relative contribution of genes, exposure to environmental pathogens, and their interaction, on the development of schizophrenia-relevant phenotypes . Preclinical modelling of G × E interactions related to schizophrenia has typically involved examining the phenotypic consequences of epidemiologically relevant but also translationally valid, experimental manipulations in various candidate risk gene mutant models . Combining an environmental challenge with a genetic mutation can produce both protective and adverse effects. It has been noted that the potential to generate such results should be incorporated within the study design and that exclusively focusing on a limited set of prespecified outcome measures may exclude the possibility of reporting such unexpected and complex bidirectional results . Particularly in the context of evidence for a shared genetic basis underlying several major neuropsychiatric disorders, the discovery of novel behavioural phenotypes in preclinical models of G × E interactions has the potential to inform us about the role of the environment in evoking diverse clinical outcomes in patients with the same mutation.
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Modelling Schizophrenia In Rodents
While it is impossible to model schizophrenia per se in mice or other rodents, three important criteria need to be satisfied in order for any experimental model to claim validity for the disorder. Firstly, the model should reflect, at least in part, the etiopathological basis of the disorder. Secondly, while research has emphasized the neurodevelopmental aspect of schizophrenia, its clinical onset is postpubertal. This fact emphasises the importance of examining the data of young animals as part of any G × E interaction modelling effort, so that the trajectory from insult during early development or young adulthood to the emergence of adult phenotypes can be established. Thirdly, the experimental model should reflect endophenotypes relevant to schizophrenia in adulthood. Endophenotypes are quantifiable, intermediate disease features that bridge the gap between the overt manifestations of schizophrenia and underlying risk genes . Earlier reviews have highlighted the value of utilising endophenotypic endpoints in preclinical genetic studies, where intermediate biological or behavioural phenotypes are less susceptible to confounding influences and are therefore easier to investigate . Schizophrenia-relevant endophenotypes include behavioural deficits and several histological/structural changes such as enlarged lateral ventricles and deficits in a specific subtype of interneurons in the cortex.
Epidemiological And Environmental Similarites And Differences
Both schizophrenia and bipolar disorder have a typical onset between adolescence and mid twenties. Males become ill earlier than females by around 2.5 years in schizophrenia a similar gender difference is also present for the first episode of mania. A male excess has often been reported in schizophrenia while most studies of bipolar patients have reported no sex difference in incidence.
The families of bipolar patients tend to be of a higher socioeconomic status than the general population, although we suspect that this finding may be confounded by general intelligence. Some studies have found an association between social deprivation at birth and schizophrenia.
One of the environmental factors that differentiate best between the disorders is urban upbringing, which has strongly been associated with the risk of schizophrenia, but not bipolar disorder. Further, studies focusing on the effect of neighborhood variation in city areas have demonstrated much more variation in rates of schizophrenia.
Obstetric events have been frequently reported to increase risk of schizophrenia such factors do not seem to predispose to bipolar disorder. An excess of winter/spring births has consistently been reported in schizophrenia. While studies have observed associations of winter birth with bipolar disorder, most have not replicated this.
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Current Methods For Genetic Analysis Of Complex Disorder
Available methods generally rely on the analysis of DNA markers in subject to determine whether the distribution of marker alleles in some way predicts the presence of disease. Some studies consider DNA variations within or near candidate gene. Many groups are now examining maps of the DNA markers throughout the genome to identify chromosomal regions likely to contain loci that have a major influence on susceptibility. These studies rely on the phenomenon of linkage, as exemplified by the fact that when ill parent transmits a disease-causing allele to children, numerous alleles at nearby loci are also transmitted because no recombination event has occurred in the region .
Challenges For The Field Of Schizophrenia Genetics
The selection of tissue for gene expression study is critical, and brain is not always necessarily the best choice of tissue. Epidemiological evidence strongly suggests that some of the primary genetic mechanisms leading to schizophrenia might reside in other tissues than brain â for example, an autoimmune mechanism that would compromise the brain â in such a case, the symptoms of schizophrenia would still reflect brain dysfunction, but would be removed from the primary noxae . A more explicit example would be if a genetic abnormality affecting an immunological response to a virus contributed to schizophrenia risk, studying the brain transcription characteristics of a neurotransmitter system would only reflect secondary neural changes to the primary immune response .
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Place Of Birth: Urbanisation
An increased risk of developing schizophrenia in urban compared with rural areas has been reported by many researchers since Faris & Dunham’s original 1939 study of inner-city Chicago, although initial reports suggested that this was due to increased migration of putatively prodromal individuals into these areas . More recent data suggest that the social drift hypothesis might not be the whole story. Reports that greatest risk is associated with urban birth rather than later urban living suggest that, whatever effect an urban environment may be having, it is acting early. It should be noted that studies looking at this in terms of deprivation have come up with some of the largest effect sizes in the literature , but on the other hand there is a clear suggestion that the effects may not be restricted to schizophrenia, as rates of many other mental disorders are increased as well . Thus, the effect may be mediated through a general increase in stress, making individuals more likely to express whatever illnesses they are predisposed to.
Social Stress And Schizophrenia
Exposure to psychosocial stressors, particularly at developmentally important time points, has been shown to both play a role in the development of a psychotic disorder and precipitate the onset of psychotic illness when the stressful experience occurs closer to the onset of the disorder . One particular social stressor which has been both linked with increased risk for schizophrenia and modelled in preclinical assays is social defeat, which refers to the defeated feeling of subordination which is experienced following an adverse social encounter . Animals studies have consistently shown that exposure to social defeat is associated with changes across several schizophrenia-related endophenotypes, as well as HPA axis function, and corticolimbic DA neurotransmission . Generally, rats or mice subjected to social defeat demonstrate impaired social behaviour, as well as increased behavioural signs of anxiety and depression .
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Causes And Symptoms Of Schizophrenia
Schizophrenia leads to various problems with thinking, emotions, and behavior. The signs and symptoms will vary from one person to the next, especially if one person is an active drug user. However, the most common symptoms include hallucinations, delusions, disorganized speech, and an impaired ability to function.
The symptoms will vary in type and severity. There will be periods of worsening symptoms, followed by remission. However, some symptoms can always be present. It may lead you to wonder, what are some causes of schizophrenia?
Patients With First Episode Of Illness
Cognitive deficits are present in first onset schizophrenia while such deficits are either nonexistent or mild in first episode of bipolar disorder. Zanelli et al confirmed that those with schizophrenia demonstrated pervasive cognitive deficits, while those with bipolar disorder showed few in particular, the schizophrenic patients showed premorbid cognitive deficits, which were absent in bipolar patients.
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Other Possible Antenatal Environmental Risk Factors
In utero exposure to noninfectious environmental agents, such as maternal stress, maternal malnutrition, maternal diabetes, smoking, and rhesus incompatibility, has also been considered.
A number of investigations have examined the relationship between experience of a stressful event during pregnancy or maternal stress more generally, and later psychosis. Risk of schizophrenia is claimed to be increased among offspring of mothers who were exposed to sudden widespread disasters while pregnant, such as the German invasion of the Netherlands in 1940 and a flood in southwest Holland in 1953. Paternal death during pregnancy was examined as a proxy for maternal stress in a study by Huttunen and Niskanen in 1978. They found a sixfold increase in risk of schizophrenia among those whose fathers had died while they were in utero, compared with those subjects who lost their fathers in infancy. Negative results have also been published indicating that considerable caution must be exercised in drawing conclusions about the role of maternal stress during pregnancy and risk of schizophrenia among offspring.,
Trauma And Social Adversities
Trauma and social adversities in different forms, either during childhood or adulthood, have been extensively investigated as potential risk factors for schizophrenia. Varese and colleagues, in a meta-analysis of case-control, prospective, and cross-sectional cohort studies, reported strong evidence that childhood adversity was associated with increased risk for psychosis in adulthood . There is an association between permanent separation from, or death of, one or both parents and psychosis , victimization and bullying and psychosis . A robust link between childhood trauma and schizophrenic symptoms has been found with childhood trauma being associated with the most severe forms of positive symptomatology in adulthood, particularly hallucinations , and affective symptoms . Life events more proximal to the onset of illness, defined as situations that bring about positive or negative changes in personal circumstances and/or involve an element of threat, have been investigated . The most recent review and meta-analysis of the relationship between life events and psychosis has suggested around a threefold increased odds of life events in the period prior to psychosis onset, with the time period under consideration ranging between 3 months and 3.6 years .
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Linkage Disequilibrium Mapping And Positional Cloning
Positional cloning is the primary strategy available for finding susceptibility genes for disorders with unknown pathophysiology. There are four stages involved in the whole process: genome scan, fine-mapping, LD mapping and functional genomics. Firstly multiple affected families are screened with a DNA marker map of all chromosomes and followed by fine-mapping in these candidate region, additional markers are genotyped 12 cM apart. The third stage is LD mapping to find the association of small sets of adjacent markers with disease, implicating one or two specific genes. Lastly functional genomics or physiological studies on animal model was initiated to establish the role of the gene and protein, effects of mutation on physiology and behaviour, and response to treatment for the disease.
Nrg1 Cannabis Exposure During Adolescence
A putative association between NRG1 genotype and cannabis-related psychosis has not yet been examined in clinical samples. A genome-wide linkage scan, and follow-up association analysis, for cannabis dependence in African-American and European-American families, revealed that NRG1 variation was associated with increased risk for cannabis dependence in African-Americans, and this effect was pronounced in females .
Cannabidiol is another psychoactive component of cannabis which has been reported to possess anxiolytic and putative antipsychotic properties . Long and colleagues examined the neurobehavioural effects of chronic cannabidiol during adulthood in TM-NRG1 mutants relative to controls . Chronic cannabidiol selectively enhanced social interaction and increased GABAA receptor binding in the granular retrosplenial cortex in TM-NRG1 mutants but had no effect on PPI or novelty-induced exploratory activity . Collectively, studies conducted on THC, synthetic cannabinoid, and cannabidiol effects in TM-domain NRG1 mutants would indicate altered sensitivity to the neurobehavioural effects of this class of drugs, in a manner which is dependent upon timing and duration of treatment.
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