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Schizophrenia is a heterogeneous and complex neuropsychiatric disorder, whose aetiology involves both environmental and genetic factors¹. In individual cases, the relative contributions of genetic and environmental factors vary. It is estimated that heritability factors contribute about 80%³⁵.

2.3.1 GENETIC FACTORS IN SCHIZOPHRENIA AETIOLOGY

Family, twin, and adoption studies have suggested that genetics play a major role in the transmission of schizophrenia^35,36. Irwing Gottesman and his colleague compiled over 40 studies in order to work out the risk of developing schizophrenia among relatives of schizophrenia probands³⁵. They found robust evidence that relatives of affected individuals are at a higher risk for schizophrenia than the general population, and that the risk in relatives is a function of the degree of genetic relatedness to the proband³⁵.

Research on molecular genetics of schizophrenia focus on the following questions, among others:

How many genes and chromosomes are involved? Where are they located? What is the mode of inheritance? What is the nature of the dysfunction? How do the genes interact with each other (including epigenetics) and environmental factors (the G x E)? ³⁷.

Shaw and his colleagues in a study published in 1998 conducted a genome wide search for evidence of loci linked to schizophrenia³⁸. The genome wide search did not find evidence for a major genetic loci for schizophrenia but, it found 12 chromosomes that had one statistically significant region at a 5% level (Chromosomes: 1,2,4,5,8,10,11,12,13,14,16, and 22).

Over the past decade, advances in genomic technology, in particular the advent of Genome-Wide Association Studies (GWAS), have led to the identification of a substantial number of genetic risk variants for schizophrenia³⁹. Researchers found around 6000 to 10000 common variants in the aetiology of schizophrenia⁴⁰. Genome-Wide Association Studies (GWAS) have identified long known candidate genes such as genes with involvement in glutamatergic and dopaminergic neurotransmission, thus providing independent support for the long-standing hypothesis that

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these pathways are involved in schizophrenia development⁴⁰. The most implicated locus is the Human Leucocyte Antigen (HLA) region. This is consistent with the hypothesis that infectious and immunological mechanisms underlie a proportion of schizophrenia cases⁴⁰.

From these results, it seems unlikely that one major locus exists for schizophrenia. It could be that schizophrenia belongs to a class of complex disorders that have a genetic predisposition.

This could be due to several genes that could produce the illness independently in different families or; several genes that act together to cause illness in susceptible individuals, with individual genes contributing minor variance: in the common- disorder- common –variance model⁴¹.

What is the mode of transmission?

Family studies provided the first clue for genetic factors in schizophrenia and it showed that the data would not fit a model of simple monogenic Mendelian transmission⁴².

One model of transmission that has been suggested is the single gene model with incomplete penetrance. Penetrance is the probability of manifesting a trait given a particular phenotype⁴³. The second mode of transmission is the polygenic model, which suggests that the liability to develop the disorder is continuously distributed within the population⁴⁴. This model is appealing because it could explain why concordance in twins increases with severity of illness and why the risk of schizophrenia increases with the number of relatives affected.

However, resolving the mode of inheritance of schizophrenia is still complicated; studies using genetic models have not been able to exclude either single gene or polygenic models. In this way, schizophrenia belongs to the group of common diseases, such as diabetes mellitus, cancer and hypertension, which has strong heritability, but no definite gene, has been implicated; and they have, therefore, been classified as being based on “Complex genetic inheritance”³⁷.

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2.3.2 NEUROCHEMICAL FACTORS IN SCHIZOPHRENIA AETIOLOGY

The dysfunction of several neurotransmitter systems like dopamine, serotonin, and glutamate is thought to play a part in schizophrenia.

The hypothesis that dopamine and dopaminergic mechanisms are central to schizophrenia and particularly psychosis has been one of the most enduring ideas about the illness⁴⁵. Dopaminergic over activity is thought to be involved in schizophrenia for several reasons. First, drugs that reduce the levels of dopamine in the brain also tend to reduce the positive symptoms of schizophrenia. Second, drugs like amphetamine that increase the levels of dopamine, also increase the psychotic symptoms of schizophrenia⁴⁶.

The dopamine hypothesis has evolved from dopamine hypothesis version 1, through version 11, to version 111⁴⁵. Version 1 could be titled “The dopamine receptor hypothesis” its emphasis is on hyperdopaminergia in the aetiology of schizophrenia⁴⁵. In the version 11; the main advance is the addition of regional specificity. This modified form of the hypothesis specifies subcortical hyperdopaminergia with prefrontal hypodopaminergia⁴⁵. The version 111, states that the presynaptic striatal dopamine synthesis capacity in schizophrenia is elevated. Hence, psychosis is, therefore, aberrant salience driven by dopamine and filtered through the individual’s existing cognitive and sociocultural schemas-thus allowing the same chemical (dopamine) to have different clinical manifestations in different cultures and different individuals⁴⁵.

The 5-hydroxytyramine (5-HT) is thought to be involved in schizophrenia because the hallucinogen Lysergic Acid Diethylamide (LSD) is a 5-HT agonist. It has been found that in schizophrenia, there is a reduced number of HT2A receptors and increase in the number of 5-HT1A receptors in the frontal cortex⁴⁷. Several hypotheses have been offered in order to explain the involvement of 5-HT in schizophrenia, including, alterations in the trophic role of 5-HT in neurodevelopment and impaired interactions between 5-HT and dopamine⁴⁷. In this regard, it is noteworthy that the second generation (so called atypical) antipsychotic drugs have significant anti-serotonergic activity⁴⁷.

Glutamate: Phencyclidine is a non-competitive antagonist of the NMDA (N-methyl-D-aspartate) type of glutamate receptor, and, like Ketamine, it produces a psychosis similar to schizophrenia.

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There is evidence that in the medial temporal lobe, glutamatergic markers are decreased and there is reduced expression of non-NMDA subtypes of glutamate receptor⁴⁷. Mechanisms that have been proposed to explain glutamatergic involvement in schizophrenia center on its interaction with dopamine, and a developmental abnormality of connections within the brain⁴⁸. 2.3.3 NEURODEVELOPMENTAL MODELS OF SCHIZOPHRENIA

Epidemiological and neuropathological findings seem to indicate that pathogenic processes early in life culminate in the development of schizophrenia⁴⁹. The neurodevelopmental hypothesis states that the origins of schizophrenia are in abnormal brain development and that the pathology originates in the middle stage of intrauterine life⁴⁹.

Other established environmental risk factors include pre-, peri-, and early postnatal complications, viral infections in childhood, childhood meningitis, being born or growing up in a densely populated urban environment, immigrant status, substance misuse and other determinants of cerebral dysfunction⁵⁰. However, research has failed to identify any environmental factors that increase the risk of schizophrenia by more than a few percentage points.