New Candidate Genes Corroborate the Genetic Theory of Schizophrenia: A Sys. Rev.

Medicina

16/04/2014

INTRODUCTION

Schizophrenia (SCZ) is a complex and multifactorial disorder whose cause is not yet agreed upon in the academic community and to which several theories of explanation have been applied.¹ The biochemical theory supports the idea that schizophrenic patients present with neurophysiological imbalances of neurochemical origin.¹ In contrast, the cerebral blood flow theory, whose validation is based on functional magnetic resonance imaging (fMRI), positron-emission tomography images and other newer diagnostic techniques, asserts that increased blood flow to regions of lower energy demand controlling specific psychomotor activities could be responsible for the hallucinations that are commonly observed in schizophrenic patients.¹ The molecular biological theory states that factors predisposing to the development of SCZ are potentially prenatal causes of this disorder. This theory in turn supports the genetic theory, arguing that the factors responsible for the direct and linear correlation between the degree of kinship and the chances of occurrence of SCZ are based on complex intragenic and intergenic relationships among the genes for SCZ, notably through single nucleotide polymorphisms (SNP), whose studies are possible due to recent advances in laboratory techniques.¹

In evaluating the extrinsic aspects of the causes of SCZ, the stress theory, drug theory, nutritional theory, viral theory and social theory should also be mentioned.¹ The stress theory states that moments of great stress on the individual or on society can trigger SCZ in a certain population at higher risk due to intrinsic factors.¹ In a similar way, the drug theory suggests that certain legal and illegal drugs or a combination of both could give rise to SCZ in a certain population at higher risk due to intrinsic factors.¹ The nutritional theory suggests that hypoproteinemia could be associated with outbreaks of SCZ, while the viral theory suggests that viral inflammation could be responsible for the onset of SCZ. Lastly, the social theory claims that social disorder is the leading cause of the onset of SCZ. All of these theories apply to certain populations at higher risk due to intrinsic factors.¹

Other theories seem to demonstrate a relative lack of understanding regarding the causes for SCZ more than the existence of several lines of study for the cause of SCZ, thus making it problematic to clarify the causes and the consequences of this disorder. 

 

OBJECTIVES

The objective of this study is to propose a hierarchy for the causes of SCZ such that the primary cause is the one proposed by the genetic theory, including the intrinsic factors such as the factors mentioned by the molecular biological theory and the biochemical theory and extrinsic predisposing factors such as the factors mentioned by the stress theory and the drug theory. Factors arising from the nutritional, viral and social theories are disregarded. The proposal of a hierarchy allows more clarity in the study of SCZ, a greater sophistication in the development of gene expression-modulating drugs for positive SCZ symptoms, and the effective use of reintegration therapies as well as similar for negative SCZ symptoms. Hence, candidate genes for SCZ, their eventual SNPs and microsatellites and their biological, physiological and chemical consequences in the schizophrenic patient, as well as genes proven to be associated with SCZ more recently in the world scientific literature, will be discussed. 

 

METHODS

A systematic review with meta-analysis was carried out via an active search of recent articles that presented candidate genes for SCZ in different populations and on several continents. For this search, the literature database website of the National Center for Biotechnology Information - PubMed.gov - was used between May 11^th 2013 and May 12^th 2013 with the keywords schizophrenia and genetics and a further title analysis of the first 200 articles obtained. The abstract analysis occurred after the title analysis and included all of the articles that had both keywords in their title, and all of the articles were written in English.

 

RESULTS

Several candidate genes for SCZ have been recently published in various scientific literature sources in 2013 that extend over a large range of chromosomal locations and are of enormous consequence for many biological tissues based on chemical inferences of their physiological natures. Haploinsufficiency of the gene ERBB4 (v-erb-a erythroblastic leukemia viral oncogene homolog 4) is associated with hyperactivity, intellectual disability, and delayed speech development, which are often present in patients with SCZ, and this genotype was observed in a 15-year old Lithuanian schizophrenic patient.²

In a study with Chinese schizophrenics of Han ethnicity, the importance of the SNP rs4402960 of the IGF2BP2 (insulin-like growth factor 2 mRNA-binding protein 2) gene in the correlation between the development of type 2 diabetes mellitus concomitant with cases of SCZ was confirmed.³ Similarly, in South Korean schizophrenics, it was also found that the SNPs rs3804099 and rs3804100 of the gene for TLR2 (toll-like receptor 2) are associated with the development of type 1 diabetes mellitus and decreased ability to concentration in cases of SCZ.⁴

A study with schizophrenics of European origin identified the SNPs rs1644731 and rs1644730 of the RDH8 (all-trans-retinol dehydrogenase), KCNQ2 (potassium voltage-gated channel, KQT-like subfamily, member 2) and APOL2 (apolipoprotein L 2) genes, which are involved in the biosynthesis of estrogens, and the SNP rs1146031 of the ACVR1 (activin A, receptor, type 1) gene, which is associated with the formation of the mesoderm, as being associated with SCZ.⁵ In that same study, the genes HSD3B1 (hydroxy-delta-5-steroid dehydrogenase, 3 beta- and steroid delta-isomerase), PSMD9 (proteasome 26S subunit, non-ATPase), KCNAB1 (potassium voltage-gated channel, shaker-related subfamily, beta member 1), SLC17A3 (solute carrier family 17, member 3), ARCN1 (archain 1), COG7 (component of oligomeric Golgi complex), STAB2 (stabilin 2), LRPAP1 (low density lipoprotein receptor-related protein associated protein 1), STAB1 (stabilin 1), CXCL16 (chemokine ligand 16), COL4A4 (collagen, type 4, alpha 4) and EXOSC3 (exosome component) were identified as being related to SCZ.⁵

A study of Chinese schizophrenics of Han ethnicity and schizophrenics of North-American origin confirmed the relevance of SNPs rs6556547, rs1816071 and rs187269 of the GABRB2 gene (gamma-aminobutyric acid A receptor, beta 2) to psychosis in SCZ patients using the PANSS (Positive and Negative Syndrome Scale) for Chinese patients of Han ethnicity and SNPs rs1816071 and rs1816073 of the GABRB2 gene to psychosis in SCZ patients using the PANSS for North American patients.⁵ In that same study, the presence of SNP rs187269 of the GABRB2 gene was also found in normal individuals positive for altruism using an altruism scale.⁶

A study with Brazilian schizophrenics found the SNP rs5992403 of the UFD1L (ubiquitin fusion degradation 1 like) gene to be responsible for the cognitive deficits observed in the SCZ sample.⁷ Moreover, a study with Chinese schizophrenic patients of Han ethnicity confirmed SNPs rs4680, rs737865 and rs165599 of the COMT (catechol-O-methyltransferase) gene, a reduction of the S2 amplitude in SNP rs4680 of the COMT gene and a reduction of the S1 amplitude in SNP rs737865 of the COMT gene as being manifested in the reduction of P50 (P50 sensory gating) and/or PPI (prepulse inhibition) in SCZ.⁸

In a study with European schizophrenic patients, the NOTCH4 (notch homolog 4), AS3MT (arsenic³⁺ methyltransferase), CNNM2 (cyclin M2) and NT5C2 (5’-nucleotidase, cytosolic 2) genes, which are associated with neuronal functions such as axonal guidance and L1 cell adhesion molecule interaction, as well as functions of the immune system such as antigen processing, cell adhesion molecules relevant to B lymphocytes and translocation to immunological synapse, are associated with SCZ.⁹ A study with Chinese schizophrenics of Han ethnicity showed that dysfunction of MYO5B (myosin 5b) is associated with changes in AMPA receptors, particularly in glutamate recycling and primary excitatory neurotransmission, which are observed in SCZ.¹⁰ Another study with a population of Chinese schizophrenic patients of Han ethnicity proved that the A-T-C haplotype of the SNC triplet (rsDAO7-rsDAO8-rsDAO13) of the DAO gene (d-amino acid oxidase), intergenic interactions between DAO and DISC1 (disrupted in schizophrenia 1), between DAO and NRG1 (neurogulin 1) and between DAO and RASD2 (RASD family, member 2) and an intragenic interaction for CACNG2 (calcium channel, voltage-dependent, gamma subunit 2) were associated with attention deficits; in addition, the intragenic interaction of DAO and intergenic interaction between DAO and PTK2B (protein tyrosine kinase 2 beta) were associated with neurophysiological dysfunctions. The extent of the intergenic and intragenic relations proves the role of DAO in glutamatergic excitation mechanisms, which are highly involved in SCZ.¹¹

In a study with healthy adolescents of European origin, the association of the SNP rs11819869 with the AMBRA1 (autophagy/beclin-1 regulator 1) gene was confirmed for several aspects of impulsivity due to the increase of BOLD (blood-oxygen level-dependent) in the medial prefrontal cortex.¹² Furthermore, a study of schizophrenic patients of North American origin showed the NR4A2 (nuclear receptor subfamily 4, group A, member 2) gene as being relevant for alterations in cell density and staining intensity on fMRI in Brodmann area 9 with successive changes in the DLPFC (dorsolateral prefrontal cortex); ¹³ another study confirmed the importance of SYNIIb (synapsin II) for alterations in the expression of synapsin IIb and successive deregulated convergent molecular mechanisms in the DLPFC, although the administration of antipsychotic drugs was capable of normalizing SYNIIb expression levels.¹⁴

In a study with healthy Italian adults, SNPs rs11780915 and rs13271367 of the PPP3CC (protein phosphatase 3 catalytic subunit gamma isoform) gene in male individuals, the SNPs haplotype (rs6459409) and diplotype (rs6459409-rs9476886) of the DTNBP1 (dystrobrevin-binding protein 1) gene in females and an SNP diplotype (rs2070586-rs3741775) of the DAO gene for both genders were found to be associated with the paranoid phenotype of SCZ, although the intergenic interaction of the SNPs of the PPP3CC gene and the DAO gene allow a 66% lower risk in women presenting with the paranoid phenotype of SCZ.¹⁵ Another study with Australian schizophrenic patients associated SNP rs2067482 of the CHRM4 (cholinergic receptor, muscarinic 4) gene with the development of negative-symptom schizophrenia resistant to standard drug amounts and concentrations, thus requiring more effective pharmacotherapy due to severe neurophysiological dysfunction.¹⁶

In a study of Polish schizophrenic patients, it was found that Val-Met in SNP rs6265 of the BDNF (brain-derived neurotrophic factor) gene was associated with the early onset of SCZ, whereas Val-Val in the same rs6265 of the BDNF gene was associated with more severe symptoms of hallucinatory behavior in SCZ according to the PANSS-G (General Psychopathology Scale of the Positive and Negative Symptoms Scale).¹⁷ Another study of Polish schizophrenics confirmed the correlation between the SNP rs2069762 of the IL-2 (interleukin 2) gene and SNP rs1800629 of the TNF-α (tumor necrosis factor-alpha) gene for the development of the paranoid phenotype of SCZ.¹⁸

In a study of North-American schizophrenic patients of African descent, 15 SNPs of genes related to ADH7, ADH1, ADH1C, ADH1B, ADH1A, ADH6, ADH4 and ADH5, which produce ADH (alcohol dehydrogenase), were found to be associated with the risk of developing SCZ.¹⁹ A study of schizophrenic patients of Sinhalese origin demonstrated an association between AKT1 (v-akt murine thymoma viral oncogene homolog 1), DISC1, DGCR6 (DiGeorge syndrome critical region gene 6) with immune dysfunction found in PBMCs (peripheral blood mononuclear cells) and an increased risk of developing SCZ, although antipsychotic treatment with risperidone or risperidone combined with haloperidol is able to normalize the expression of these genes.²⁰

In a study of Japanese schizophrenic patients, it was noted that the up-regulation of the ZNF804A gene (zinc finger protein 804A) is capable of successive up-regulation of the ANKRD1 (ankyrin repeat domain 1), INHBE (inhibin, beta E), PIK3AP1 (phosphoinositide-3-kinase adapter protein 1) and DDIT3 (DNA-damage-inducible transcript 3) genes, of which DDIT3 is associated with the signaling pathway of TGF-β (transforming growth factor-β), which is important in cell differentiation. These genes are associated under such conditions with dysfunction in cell signaling pathways and the risk of developing SCZ.²¹ A study with Belgian schizophrenic patients detected the association of SNPs rs6928499, rs1535255 and rs2023239 of the CNR1 (endocannabinoid receptor 1) gene with a high prevalence of MetS (metabolic syndrome) in schizophrenic patients, thus demonstrating the relationship of this gene with metabolic disorders and SCZ.²²

In a study of schizophrenic patients of northern Indian origin, the participation of SNP rs35753505 of the NRG1 gene in emotion processing and of SNP rs6994992 in the NRG1 gene in attention span was shown, thus associating them with the emotional and attention disorders found in SCZ.²³ A study of South Korean schizophrenics demonstrated the expression of SNPs rs9357271 and rs3923809 of the BTBD9 (BTB domain containing 9) gene in antipsychotic-induced restless legs syndrome in schizophrenic patients.²⁴

A study of Palauan patients with schizoaffective disorder demonstrated the involvement of SLC1A1 (solute carrier family 1, member 1) in psychotic episodes because its deletion is accompanied by the deletion of 59 amino acids of the protein, among which are the amino acids associated with the first transmembrane Na²⁺-dicarboxylate symporter domain, thus impairing glutamatergic transmission. The pathophysiology of the SLC1A1 deletion confirms the association of the psychiatric spectrum of SCZ with the psychological spectrum of bipolar disorder.²⁵ Finally, a study of Chinese schizophrenic patients showed that the intergenic relationship between the DAOA (D-amino acid oxidase activator) gene and PSEN2 (presenilin 2) gene was associated with SCZ; additionally, SNP rs2391191 of the DAOA gene was able to alter the ReHo (regional homogeneity) in the bilateral culmen, left putamen and left cuneus by impairing glutamatergic modulation.²⁶

 

CONCLUSIONS

The recent boom in candidate genes for SCZ confirms the hierarchy proposed herein of the genetic theory as a cause for SCZ, followed by the intrinsic consequence factors mentioned in the molecular biological theory and the biochemical theory as well as the extrinsic predisposing factors mentioned in the stress theory and the drug theory. There are several SNPs of different genes that are associated with the pathologic changes found in biological tissues and with the physiological regulation of several neural circuits, of metabolism, of embryonic development and of immune system development and that are also involved in the chemical interactions between various endogenous structures and those obtained from ingestion or exposure to risk situations. The interrelationship between pharmacotherapy and improved SCZ symptoms is sometimes maintained by the best expression of several candidate genes for SCZ as well as the inadmissibility of risk behaviors that may alter chemical interactions between various structures, allowing silencing or the late onset of SCZ, thus providing a better prognosis.

 

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