As a reminder, like all the other Filters discussed (i.e. the instincts, behavioral preferences, default ways of interpreting our environment and the way we interact with it, etc.), the Reality Perception Personality Spectrum Ensemble, is not at all likely to be understood as a trait solely via the expression of one gene. Rather, multiple genes, in concert with multiple other filters are likely necessary to understand completely the Reality Perception Ensemble. It is the result of an ensemble of components - their presence and their expressions. Including the environment itself.

Specifically, increasing evidence suggests that schizophrenia is genetically heterogeneous. And, recurrence risk data are also consistent with monogenic inheritance of large-effect alleles in a proportion of people with schizophrenia, but with different alleles for different families.

A few identified genetic variants have been seen also to impact schizophrenia, and thus the Reality Perception Personality Spectrum Ensemble. Selected links to representative research on these and others will be added in the next version of this chapter:

• Dysbindin (Dystrobrevin-binding protein 1) - In humans, dysbindin is encoded by the DTNBP1 gene. A strong association was found between expression of a particular dysbindin allele and a clinical expression of schizophrenia in some pedigree-based family-association studies of families with a history of schizophrenia. This link has not been established in all the case control samples tested, implying genetic heterogeneity. It is also highly likely that there are several or many different mutations within the dysbindin gene that are responsible for schizophrenia (allelic heterogeneity.)
• Neuregulin-1 (NRG1) - In humans, Neuregulin-1 is encoded by the NRG1 gene. Careful regulation of the amount of Neuregulin 1 must be maintained in order to preserve an intricate balance between excitatory and inhibitory connections within the central nervous system (CNS). Any disruption in this inhibitory system may contribute to impaired synaptic plasticity, a symptom endemic in schizophrenic patients.
• D-amino acid oxidase activator (DAOA, also known as G72) - This gene encodes a protein that may function as an activator of D-amino acid oxidase, a gene associated with schizophrenia in a number of studies. In separate studies, some DAOA alleles have also been shown to confer susceptibility to bipolar disorder.
• D-amino acid oxidase (DAAO, also DAO, OXDA, DAMOX) - Oxidizes D-amino acids to the corresponding imino acids, producing ammonia and hydrogen peroxide. D-amino acid oxidase has been connected to the brain D-serine metabolism and to the regulation of the glutamatergic neurotransmission. Degrades the gliotransmitter D-serine, a potent activator of N-methyl-D-aspartate (NMDA) type glutamate receptors. DAAO is a candidate susceptibility gene and together with G72 may play a role in the glutamatergic mechanisms of schizophrenia.
• Regulator of G-Protein Signaling 4 (RGS₄) - In humans, is encoded by the RGS4 gene. A number of studies associate the RGS4 gene with schizophrenia, while some fail to detect an association (consistent with genetic heterogeneity for the causes of schizophrenia.) May be important in the development of tolerance to opioid drugs.
• the 22q11.2 deletion (most of the deletions (around 90%) are 3Mb in size, which includes approximately 60 genes. The remaining microdeletions (~10%) are 1.5Mb in size and include approximately 35 genes. Most the genes within the microdeletions are expressed in the brain.) Five genes located in the 1.5Mb region, which confer risk of schizophrenia based on studies of human genetics and using animal models, are:
  • Catechol-O-methyltransferase (COMT) - In humans, catechol-O-methyltransferase is encoded by the COMT gene. Involved in the inactivation of the catecholamine neurotransmitters (such as dopamine, epinephrine, and norepinephrine). A functional single-nucleotide polymorphism (SNP) (a common normal variant) of the COMT gene results in a valine to methionine mutation at position 158 (Val158Met), reducing COMT activity, and thus resulting in higher synaptic dopamine levels following neurotransmitter release. The gene variant has been shown to affect cognitive tasks broadly related to executive function, such as set shifting, response inhibition, abstract thought, and the acquisition of rules or task structure. Comparable effects on similar cognitive tasks, the frontal lobes, and the neurotransmitter dopamine have also all been linked to schizophrenia. Reduced COMT activity has also been linked to obsessive-compulsive disorder (OCD).
  • Proline d-hydrogenase (PRODH2) (encoding an enzyme required for proline metabolism)
  • TBX1 (encoding a transcription factor involved in the embryonic development of multiple tissues and organs)
  • ZDHHC8 (encoding a palmitoyl transferase enzyme)
  • DGCR8 (a key gene for microRNA (miRNA) processing and synthesis).
• miRNAs belonging to miR-17/92 cluster and miR-106a/b (Those miRNAs are reported to target p38α)
• p38α (known to drive gliogenic differentiation)
• Glial fibrillary acidic protein (GFAP), a gliogenic (astrocyte) marker. GFAP is thought to help to maintain astrocyte mechanical strength, as well as the shape of cells but its exact function remains poorly understood. Decreases in GFAP expression have been reported in Down's syndrome, schizophrenia, bipolar disorder and depression.
• Microtubule-associated protein 2 (MAP2) - In humans, is encoded by the MAP2 gene. A neuronal marker.
• Disrupted in Schizophrenia 1 (DISC1) - In humans, is encoded by the DISC1 gene. Several studies have shown that unregulated expression or altered protein structure of DISC1 may predispose individuals to the development of schizophrenia, clinical depression, bipolar disorder, and other psychiatric conditions.
• Metabotropic Glutamate Receptor-3 (GRM3) (See Supplementary Discussion below). The mGluR3 receptor encoded by the GRM3 gene has been found to be associated with bipolar affective disorder, schizophrenia and alcoholism. GRM3 is likely to contribute to the genetic susceptibility of a variety of mental disorders.
• Protein phosphatase 1 regulatory subunit 1B (PPP₁R₁B) (also known as Dopamine- and cAMP-regulated neuronal phosphoprotein (DARPP-32)) - In humans, is encoded by the PPP1R1B gene. Click here, and click here also. There is some support for a role of the gene in schizophrenia, as well as being involved in the drug and alcohol abuse, and gambling addiction.
• Vasoactive intestinal peptide receptor 2 (VIPR2, also known as VPAC2) - In humans, is encoded by the VIPR2 gene. Regulates brain neuron development and activity. Research using VPAC2 knockout mice implicate it in the function of the circadian clock, growth, basal energy expenditure and male reproduction. Interestingly, VIPR2 may play a role in Schizophrenia.
• G4 (involved in eliminating the connections between neurons - a process called "synaptic pruning,")
• Complement component 4 (C4) - Involved in the intricate complement system, originating from the human leukocyte antigen (HLA) system. It serves a number of critical functions in immunity, tolerance, and autoimmunity. C4 is also being investigated for the role it may play in schizophrenia risk and development. May be involved in synaptic pruning.
  
  
• Biological insights from 108 schizophrenia-associated genetic loci, Nature 511, 421-427 (24 July 2014)
• Genetic study provides first-ever insight into biological origin of schizophrenia, Press releases / 01.26.16, The Broad Institute
  
  
• others not included here.

Supplementary Discussion genes of particular interest (from the "Biological insights from 108 ..." Nature article above) (for the full discussion of supplementary information, click here):

"Genes within associated loci are highlighted here where we identify them to be of particular interest with respect to current hypotheses of schizophrenia aetiology or treatment. However, we stress that association only implies the existence of one or more risk variant at the associated locus rather than that a specific gene is responsible for the association."

• Therapeutic targets (G protein coupled receptor signalling):
  • DRD2 (11q23.2) - Dopaminergic neurotransmission is integral to cognition, reward, motivation, learning and memory. The dopamine type 2 receptor subtype is of particular interest in psychiatry because blockade remains a necessary and sufficient condition for antipsychotic activity, despite attempts to develop alternatives.
  • GRM3 (7q21.12) - mGluR3 is a metabotropic glutamate receptors predominantly expressed in astrocytes which, along with GRM2 ( mGluR2), has been extensively explored as potential therapeutic target in schizophrenia.
• Glutamatergic neurotransmission:
  • GRIN2A (16p13.2) - The NMDA receptor subunit GRIN2A (NR2A) is a key mediator of synaptic plasticity. NMDA receptor channel blockers such as ketamine and NMDA autoantibodies mimic some of the symptomatology of schizophrenia in humans. Mutations have been reported in focal epilepsies, ID, autism, and schizophrenia.
  • GRIA1 (5q33.2) - Glutamate receptor 1 (GluR1, GluA1) is a subunit of an AMPA (non-NMDA) receptor that mediates fast synaptic transmission. It is involved in activity-dependent synaptic targeting of AMPARs and is critical for dendritic organization of receptors and hippocampal synaptic transmission and plasticity.
  • SRR (17p13.3) - Serine racemase catalyzes L-serine racemization to D-serine, an essential coagonist and activator of NMDA receptors. Altered D-serine levels have been associated with schizophrenia.
  • CLCN3 (4q33) - CLC-3 is a voltage-gated chloride channel localized to glutamatergic synapses in the hippocampus, where it modulates plasticity. Knockout mice also have altered GABAergic function and complete postnatal degeneration of the hippocampus, suggestive of a causal relationship to network connectivity.
  • Other glutamate relevant genes include GRM3 (see above) and SLC38A7 (16q21) encoding SNAT7, an L-glutamine preferring neuronal amino acid transporter that may be important for the reuptake and recycling of glutamate.
• Neuronal calcium signalling:
  • CACNA1I (22q13.1) - CACNA1I is the pore forming alpha subunit of the Ca_v3.3 T-type calcium channel. Activation triggers synaptic plasticity and long-term potentiation when co-activated with NR2B-containing NMDA receptors. Several antipsychotics block T-type channels, although efficacy through this blockade has not been demonstrated.
  • RIMS1 (6q12-13) - RIMs are multi-domain proteins that tether calcium channels to synaptic active zones, dock and prime synaptic vesicles for release, mediate presynaptic plasticity and facilitate neurotransmitter release.
  • Prior and other implicated calcium signalling genes include: CACNA1C, CACNB2, CAMKK2, NRGN, ATP2A2. Mutations in ATP2A2 cause Darier's Disease and co-segregate in some families with bipolar disorder and psychosis.
• Synaptic function and plasticity:
  • KCTD13 (16p11.2) - Polymerase Delta-Interacting Protein 1 is a substrate-specific adapter of a BCR (BTB-CUL3-RBX1) E3 ubiquitin-protein ligase complex involved in regulation of cytoskeleton structure. It lies within a pathogenic CNV at 16p11.2 associated with neurodevelopmental disorders and brain and body size phenotypes. Zebrafish and mouse studies have implicated the ortholog of KCTD13 as the dosage-sensitive driver gene in this CNV. A previous GWAS study of schizophrenia and bipolar disorder previously implicated this locus.
  • NLGN4X (Xp21.33-32) - Neuroligins induce localized formation of functional neurotransmitter release sites in axons, by aggregating neurexins and inducing formation of glutamatergic and GABAergic presynapses. Nlgn4 is present at both excitatory and inhibitory postsynapses, and may modulate the pre-synaptic calcium channel population through its interaction with neurexins. Mutations are associated with autism.
  • IGSF9B (11q25) - IgSF9b is a brain-specific adhesion molecule that is strongly expressed in GABAergic interneurons, localized to hippocampal and cortical inhibitory synapses where it is required for their development into interneurons.
  • CNTN4 (3p26.3) - Contactins are axon-associated cell adhesion molecules that function in neuronal network formation and plasticity. CNTN4 is highly expressed in the brain, and deletions and mutations have been associated with ASDs.
  • MEF2C (5q14.3) - A transcription factor regulating neurogenesis, excitatory synapse number, dendrite morphogenesis and differentiation of post-synaptic structures. Late embryonic forebrain deletion causes dramatic increase in excitatory synapse number and impairment of hippocampus-dependent learning and memory. Earlier deletion results in abnormal neuronal migration into the neocortex. MEF2C haploinsufficiency causes severe intellectual disability.
  • PTN (7q33) - Pleiotrophin is a developmentally regulated neurite growth-promoting factor (NEGF) family cytokine/growth factor. It is expressed in an activity-dependent manner in the hippocampus where suppresses long term potentiation.
  • CNKSR2 (Xp22.12) - CNK2 is a scaffold/adaptor protein that mediates the MAPK pathway downstream from Ras. Expression is restricted to neuronal tissues where it localizes to dendritic spines and forms a complex with the PSD. It plays a role in assembly of synaptic complexes at the postsynaptic membrane and coupling of signal transduction to membrane/cytoskeletal remodelling. Loss of function CNKSR2 mutations are a cause of non-syndromic X-Linked intellectual disability.
  • PAK6 (15q14) - PAK6 is a highly brain expressed serine/threonine protein kinase associated with neurite outgrowth, filipodia formation and cell survival. PAK6 shows functional redundancy with PAK7 and double knockout mice have specific deficits in learning and memory. A rare inherited duplication at PAK7 has been associated with increased risk of schizophrenia and bipolar disorder.
  • SNAP91 (6q14.2) - SNAP91 (AP180) is enriched in the presynaptic terminal of mammalian neurons where it regulates synaptic vesicle endocytosis through a clathrin-dependent reassembly process. Together with CALM it establishes the polarity and controls the growth of axons and dendrites in embryonic hippocampal neurons.
• Other neuronal ion channels:
  • KCNB1 (20q13.13) - Kv2.1 is a delayed rectifier VGKC in the drosophila shab-related subfamily. It is abundantly expressed in the cortex and hippocampus, where it regulates neuronal excitability, action potential duration, and tonic spiking.
  • HCN1 (5p21) - HCN1 is a potassium channel pore forming subunit and a major contributor to the inward hyperpolarization-activated cation current (I_h) current in the brain, which regulates neuronal excitability, rhythmic activity and synaptic plasticity. HCN1 is widely expressed in brain and is enriched in distal apical dendrites. It is also a pacemaker in cardiac tissue.
  • CHRNA3, CHRNA5, and CHRNB4 (15q25.1) - Nicotinic acetylcholine receptors (nAChRs) form ligand-gated ion channels in certain neurons and also on the presynaptic and postsynaptic sides of the neuromuscular junction. This cluster of nAChR genes has previously been reproducibly associated with nicotine dependence, smoking behaviours, and lung cancer risk.
• Neurodevelopment:
  • FXR1 (3q26.33) - FXR1P is a member of the family of RNA binding proteins that includes FMRP, mutations in which cause Fragile X syndrome. FXR1P is found in dendritic spines in the mouse hippocampus and targets mRNAs and microRNAs including brain specific miRNA9 and miR-24.
  • SATB2 (2q33.1) - A DNA binding protein that binds nuclear matrix attachment regions, regulating transcription and chromatin remodeling. Expression is restricted to post-mitotic, differentiating neurons in the neocortex, where it acts as a determinant for upper-layer projection neuron identity during cortical development. SATB2 deletion causes 2q32-q33 deletion syndrome and duplication manifests with ASD.
  • Additional molecules involved in neurodevelopment include: PODXL, BCL11B, TLE1, TLE3, FAM5B

- - - End of Supplementary Discussion section. - - -

It is worth noting that as part of the normal mechanism of brain maturation, a significant amount of synaptic pruning occurs, especially during a period that extends from late adolescence through to early adulthood. The microglial cells in the brain are involved in carrying this process out. They are related to immune system cells called macrophages, and carry out a similar function. They also migrate to parts of the brain that have been damaged by stroke or disease, eating up dead neurons through a process called phagocytosis, and clear away any cellular debris left behind.

Because the brain apparently produces more neurons than it needs, more synaptic connections are formed than are required as well. Eventually, the excess connections are removed via synaptic pruning, reducing the number of synapses by as much as 40% normally. The microglia are involved in this pruning. How they determine which synapses to eliminate and which to leave is unknown at this time. However, what has been observed is that under conditions where synaptic pruning is occuring at a greater level than normal, reducing the remaining synapses to a level below normal, various cognitive deficits are seen, including the observation of schizophrenia in affected patients. Schizophrenia is also known to often begin during this stage of life. Thus, aberrant pruning may be at play in the development of the disease.

Another way to regard this is that in addition to the genes coding for the individual components involved in the organically implemented ability for us to discern the Real from the Unreal, how these are used in the creation of the brains is important (obviously). And thus, the architecture of the structures they are used to create is important. Remove too much of it, and the ability to discern the Real from the Unreal, implemented in the way our brains are wired, becomes degraded.

A very consequential paper, "Biological insights from 108 schizophrenia-associated genetic loci" is reproduced here and further enhanced (organized) by ConserveLiberty to emphasize an appreciation for the number of potential individual components that may be involved in schizophrenia. Check it out if you haven't already and your level of scientific interest takes you there.

→ The Section above was last updated 13 Dec 2016 10:10 PST ←

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