The Genetics of Schizophrenia
The genetics research is huge and just becomes more and more diverse. Clearly, hundreds of genetic variations are linked to causing an increased risk of schizophrenia at dozens of different sites in the genome and the brain. Obviously, many of the variations are causing different dysfunctions in the brain which all end up looking like some variety of schizophrenia. Some day, they may lead to different prevention and treatment strategies, but that day hasn't arrived yet. At present, there is still no clinical value in genetic testing for any psychiatric disorder.
The DISC-1 (Disrupted in Schizophrenia Gene-1), neuregulin, dopamine receptor, FOXP2, GABA receptor, GRIN1 and GRIN2 NMDA receptors, methylenetetrahydrofolate reductase, PLXNA2, and dysbindin gene polymorphisms are most closely associated with increased rates of schizophrenia although many other polymorphisms are associated with an increased risk. The Velo-Cardio-Facial Syndrome 22q11 Deletion may cause between 2% and 6% of schizophrenia. Polymorphisms of many other genes have been identified it various populations, but need to be replicated. Many I have not included on this page because it is so overwhelming.
Genetics is a very complex science with unexpected variations being discovered almost monthly. For instances, many diseases and perhaps some strengths are caused by people having more than two copies of certain genes and only one copy of others.
22q11 Microdeletions Increased: There is a higher-than-expected frequency of 22q11 microdeletions in patients with schizophrenia and approximate 20-30% of individuals with 22q11 microdeletions develop schizophrenia or schizoaffective disorder in adolescence and adulthood. A high rate of 22q11 microdeletions was reported for 47 patients with Childhood Onset Schizophrenia, a rare and severe form of schizophrenia with onset by age 13. It is therefore likely that this 1.5-Mb region contains one or more genes that predispose to schizophrenia. In three independent samples, researchers found evidence for a contribution of the PRODH2/DGCR6 locus in 22q11-associated schizophrenia. There was also an unusual pattern of PRODH2 gene variation that mimics the sequence of a linked pseudogene. Several of the pseudogene-like variants identified result in missense changes at conserved residues and may prevent synthesis of a fully functional enzyme. Proc Natl Acad Sci U S A 2002 Mar 12
22qDS No Different in Schizophrenia: Patients with 22qDS-schizophrenia (22q11 Deletion Syndrome) had higher excitement subscale scores and less lifetime substance use than the comparison patients with schizophrenia, but no significant differences in anxiety-depression symptom severity were found between the groups. These findings indicate that the core clinical schizophrenia phenotype would not distinguish individuals with a 22qDS subtype from those with schizophrenia who did not have the 22qDS subtype. U Toronto. The schizophrenia phenotype in 22q11 deletion syndrome. Bassett AS, Chow EW, et al. Am J Psychiatry. 2003 Sep;160(9):1580-6
47,XXY, 47,XXX Reduce Amydala Size: An excess of 47,XXX and 47,XXY karyotypes was found in cytogenetic screening studies of individuals with schizophrenia. The study found reduced amydala volume and increased mild psychotic difficulties in men and major ones in women. Stanford. Am J Med Genet 2002 Jan 8;114(1):93-8
5-HT2A Receptor Gene C/T(102) Polymorphism Linked: Genetic association schizophrenia and a silent C/T(102) polymorphism in the 5-HT2A receptor gene (5-HT2AR) mechanisms underlying this association remain unknown. Expression of allele "C" in the temporal cortex of normal heterozygous individuals was significantly lower than the expression of allele "T" (P < 0.0001). Total levels of 5-HT2AR mRNA and protein in normal individuals with the C/C genotype were lower than in individuals with the T/T genotype. Similarly to normal individuals, allele "C" to allele "T" ratio in heterozygous schizophrenics was reduced (P < 0001). This ratio was independent of neuroleptic treatment history. By contrast, total levels of 5-HT2AR mRNA correlated inversely with neuroleptic free interval prior to death (P < 0.001) suggesting a reversible neuroleptic effect. Total levels 5-HT2AR mRNA in neuroleptic free (> 26 weeks) schizophrenics (n = 11) were significantly lower than in controls (P = 0.03). The data suggest that increased prevalence of allele "C" among schizophrenics may be due to intrinsically low expression of this allele, which may contribute to a deficit in 5-HT2AR. J Neurosci Res 2002 Mar 15;67(6):812-22
5-HT2A Receptor Gene Polymorphism Not Linked: A large Polish study of 235 schizophrenic patients and 344 controls found no linkage. Association Analysis of Serotonin 2A Receptor Gene T102c Polymorphism and Schizophrenia. Czerski PM, Leszczynska-Rodziewicz A, Dmitrzak-Weglarz M, Kapelski P, Godlewski S, Rybakowski J, Hauser J. World J Biol Psychiatry. 2003 Apr;4(2):69-73
5-HTTT Serotonin Transporter Gene Variant Associated with Hallucinations: The serotonin transporter is important in serotonin regulation. Polymorphism in the promoter region of the 5-HTTT gene found associations with anxiety in normals. 50 drug free schizophrenic or schiz-affective patients were studied. Those with full II polymorphism had more intense hallucinations than those with Is or ss. Malhotra, NIMH, Mol Psychiatry ’98;3:328
Adenomatous Polyposis Coli (APC) Tumor Suppressor Gene Polymorphisms a Risk Factor: In comparing leukocytic gene expression patterns of six pairs of patients with schizophrenia and healthy controls by microarray, APC expression levels were significantly increased in all patients compared to healthy controls. To confirm the findings of microarray analysis, researchers measured expression levels of APC in the leukocytes from 30 relapse patients taking antipsychotic medication, 29 first-episode drug-naive patients, and 30 healthy controls using real-time quantitative reverse transcription (RT)-polymerase chain reaction (PCR). APC expression levels were significantly increased in leukocytes of schizophrenics both taking and not taking antipsychotic medication and hence the increase of APC expression was not due to antipsychotic medication. APC is located at 5q21-22, which has been previously reported to be linked with schizophrenia. In transmission disequilibrium test (TDT) and TDT based on haplotypes to search for the association between schizophrenia and APC by examining 163 parent-offspring trios of Chinese descent. Three single-nucleotide polymorphisms (SNPs) (rs2229992, rs42427, rs465899) at the exon region of APC. TDT showed that the three SNPs are significantly associated with schizophrenia (P<0.05; 4.15, P<0.05; 8.49 P<0.01, respectively) with a significant association between the APC haplotypes from rs2229992-rs42427-rs465899 and schizophrenia ( P<0.001). The C-A-T haplotype has a frequency of more than 57% and has a strong association with schizophrenia (P<0.001). These results indicate that the APC may be a candidate gene conferring susceptibility to schizophrenia and also may be associated with reduced vulnerability to cancer in schizophrenia. The tumor suppressor adenomatous polyposis coli gene is associated with susceptibility to schizophrenia. Cui DH, Jiang KD, et al. Fudan University, Shanghai, China. Molecular Psychiatry 15 March 2005
AKT1 Polymorphisms Linked to Schizophrenia: Involvement of AKT signaling pathways in schizophrenia has been recently suggested, on the basis of several lines of evidence. In addition to impairment of protein-levels and phosphorylation levels in the pathway, association of DNA sequence variants in the AKT1 gene with schizophrenia has been detected in a family sample. In a sample of 79 sib-pair families with schizophrenia using the five single nucleotide polymorphisms (SNPs) of the original study and two additional SNPs in the neighborhood of the SNP for which association had been reported, researchers found significant association for single markers (p = .002) and multilocus haplotypes (p = .0013) located in the same region as has been reported in the previous study. Further Evidence for Association of Variants in the AKT1 Gene with Schizophrenia in a Sample of European Sib-Pair Families. Schwab SG et al. University of Western Australia, Perth. Biol Psychiatry. 2005 Jul 15
APOE ep4 Gene Lowers Ketamine Impact: Apolipoprotein E epsilon 4 allele was associated with fewer positive symptoms in schizophrenia. Study of 18 individuals found less psychotic effect from ketamine in those with that allele. Malhotra, NIMH, Neuropsychopharm ’98;19:45; Clozapine also blunts ketamine effect. Biol Psychiatry ’97;42:664
Brain Derived Neurotrophic Factor Affect Hypocampal Volume: MRI hippocampal alterations are in the pathogenesis of schizophrenia. Brain-derived neurotrophic factor (BDNF) is widely expressed in the hippocampus. BDNF gene variant val66met is a functional and abundant missense polymorphism in the coding region of the BDNF gene. In 19 patients with first-episode schizophrenia and 25 healthy volunteers, val/val homozygotes (N=27) had larger volumes of the hippocampal formation compared to val/met heterozygotes (N=17). Val66met genotype accounted for a greater proportion of the variance in the volume of the hippocampal formation in patient compared to healthy adults. Brain-derived neurotrophic factor Val66met polymorphism and volume of the hippocampal formation. Szeszko PR, Lipsky R, et al. Albert Einstein. Molecular Psychiatry 15 March 2005
Brain Derived Neurotropic Factor Polymorphisms Associated with Major Depression: In a single-marker and haplotype analyses using three BDNF polymorphisms in 2,376 individuals (465 MDD, 281 BPAD, 533 schizophrenia, and 1,097 control subjects), single-marker analysis did not provide strong evidence for association. Haplotype analysis of marker combination rs988748-(GT)(n)-rs6265 produced nominally significant associations for all investigated phenotypes (global p values: MDD p = .00006, BPAD p = .0057, schizophrenia p = .016). Association with MDD was the most robust finding and could be replicated in a second German sample of MDD patients and control subjects (p = .0092, uncorrected). The finding in schizophrenia appeared to be attributable mainly to the presence of depressive symptoms. Evidence for a Relationship Between Genetic Variants at the Brain-Derived Neurotrophic Factor (BDNF) Locus and Major Depression. Schumacher J, et al. Institute of Human Genetics. Biol Psychiatry. 2005 Jul 6
CAG Repeats in hSKCa3/KCNN3 calcium-activated potassium channel gene Linked in Jews: In 1999 reported that long CAG repeats in the calcium-activated potassium channel gene hSKCa3/KCNN3 are associated with higher negative symptom dimension scores in Ashkenazi Jewish Israeli schizophrenia patients (Mol Psychiatry 1999 May;4(3):254-60). 2nd study investigated whether a symptom polymorphism of schizophrenia is associated with both the CAG repeat numbers and the difference in allele sizes. We tested the association of CAG repeats with symptom models of schizophrenia in 117 unrelated Jewish patients. A multivariate analysis (MANOVA) of two models of schizophrenia with the repeat distribution and the difference in allele sizes was performed. Positive association of the number of CAG repeats with negative syndrome, anergia, activation, and paranoid symptoms. In addition, nonparanoid schizophrenia patients who had differences in allele sizes were characterized by earlier onset of illness. The combined effect of long CAG repeats and the differences in allele sizes contribute to symptom expression of schizophrenia, particularly on the anergia-activation-paranoid axis. Japanese study of 115 schiz found no increase CAGs in hKCa3. Psychiatr Genet 2001 Dec;11(4):227-9; KCNN3 is a member of the gene family, KCNN1-4, encoding the small and intermediate conductance calcium-activated potassium channels. Long CAG-repeat alleles of this gene have been found to be over-represented in patients with schizophrenia in a number of population-based association studies, and this gene maps to human chromosome 1q21, a region recently implicated in schizophrenia by linkage. J Hum Genet 2001;46(8):463-70; Altered activity of DA midbrain neurons is a key finding in schizophrenia. differential SK3 channel expression is a critical molecular mechanism in DA neurons to control neuronal activity. J Neurosci 2001 May 15;21(10):3443-56; Didn’t find KCNN3 CAGs in schiz in India. Am J Med Genet 2000 Dec 4;96(6):744-8; Not found in NE U.S. Mol Psychiatry 2000 May;5(3):237-8; Studies in Germany and Ireland also failed to replicate.
CAPON Enzyme Gene Polymorphism Linked: There is a linkage of markers on chromosome 1q22 to schizophrenia. Within this linkage region, researchers found a significant linkage disequilibrium between schizophrenia and markers within the gene for carboxyl-terminal PDZ ligand of neuronal nitric oxide synthase (CAPON), a protein in human dorsolateral prefrontal cortex (DLPFC). Quantitative real-time PCR analysis of RNA from the DLPFC in 105 individuals (35 with schizophrenia, 35 with bipolar disorder, and 35 psychiatrically normal controls) revealed significantly (p < 0.005) increased expression of an isoform of CAPON that consists of the terminal two exons of the gene in both schizophrenia and bipolar disorder. This increased expression was significantly associated (p < 0.05) with genotype at three single-nucleotide polymorphisms previously identified as being in linkage disequilibrium with schizophrenia. Based on the known interactions between CAPON, neuronal nitric oxide synthase (nNOS), and proteins associated with the N-methyl-D-aspartate receptor (NMDAR) complex, overexpression of either CAPON isoform would be expected to disrupt the association between nNOS and the NMDAR, leading to changes consistent with the NMDAR hypofunctioning hypothesis of schizophrenia. Increased Expression in Dorsolateral Prefrontal Cortex of CAPON in Schizophrenia and Bipolar Disorder. Xu B, et al. Rutgers University. PLoS Med. 2005 Sep 13;2(10):e263; While Canadian and Chinese studies found linkages, a British study failed to find a linkage. Biol Psychiatry. 2005 Sep 30
COMT Dopamine Gene Variant Increases Risk of Schizophrenia: Many different genetic abnormalities can cause schizophrenia. In a new study by Allan Reiss et al of Stanford University, children who possess one copy of an abnormal gene variant for the COMT gene on chromosome 22 are much more likely to develop schizophrenia. This deletion of one copy of the normally available two healthy genes occurs in 1 of 4,000 births. 30% of 24 children followed eventually developed schizophrenia. These children were also prone to heart disease, cleft palate, and learning disorders. The COMT gene produces a protein that breaks down dopamine. It has two normal variant, one stronger at breaking down dopamine than the other. Children with one abnormal variant and the normal weak variant were the most affected with greater shrinkage of the prefrontal brain. The defect means that these individuals have too much dopamine. Nature Neuroscience 11/05.
COMT Not Involved in Huge Study: In a study of more than 2,800 individuals, including almost 1,200 with schizophrenia, from case-control and family-based European association samples, there was no support for the hypothesis that a valine/methionine polymorphism in the COMT gene influences susceptibility to schizophrenia or the hypothesis that a COMT haplotype influences susceptibility to schizophrenia in Ashkenazi Jewish and Irish subjects. No Association Between Schizophrenia and Polymorphisms in COMT in Two Large Samples. Williams HJ, et al. Cardiff University, UK. . Am J Psychiatry. 2005 Sep;162(9):1736-8; A 2005 Chinese study found the same result. Mol Psychiatry. 2005 Aug 30; Similarly, in Koreans. Psychiatry Res. 2005 Sep 15;136(2-3):83-91.
COMT Polymorphism May Be Involved: A single point mutation in the COMT gene (COMT degrades dopamine in synapses) causes a 75% reduction in the activity of COMT. This increases dopamine activity in the prefrontal cortex to significantly improve executive functioning and is responsible for 4% of the human variation of attention and executive functioning. It is not found in great apes, was proposed as a potential factor in the evolution of the cortex, and, therefore, of mankind itself. And the gene encoding the more effective form of COMT has been shown to be significantly more prevalent in patients with schizophrenia and is a susceptibility gene for schizophrenia. Weinberger DR. Molecular biology and genetics of cortical function in schizophrenia. American Psychiatric Association 155th Annual Meeting; May 18-23, 2002; Philadelphia, Pennsylvania. Industry-supported Symposium No. 24E.
COMT Gene Abnormality in 20% of Schizophrenics in Israel: Study of 1000 Jews of European descent. Amer J Human Genetics 12/02.
COMT Gene Variant Increased in Schizophrenics: a common genetic variant in an enzyme involved in dopamine degradation in prefrontal cortex is linked to poor memory function and increased susceptibility to schizophrenia (Proceedings of the National Academy of Sciences USA 2001;98:6917-22.). schizophrenia have increased dopamine receptor levels in their brains and increased homovanillic acid, a metabolite of dopamine, in their urine. Catechol-o-methyltransferase exists in two allelic forms, which differ only by a single amino acid—methionine or valine at position 108/158. An individual may have two valines, two methionines, or one each of methionine and valine. When two valines are present, there is a high level of catechol-o-methyltransferase, leading to increased catabolism of dopamine. But when an individual has an identical pair of the methionine variants, there are low levels of catechol-o-methyltransferase and relatively high levels of dopamine in the prefrontal cortex. examined 175 adults with schizophrenia, 219 unaffected siblings, and 55 controls. The subjects were matched for age, sex, IQ, and education. All study subjects were aged 18-60 years, had a premorbid IQ of over 70 and were free of head trauma and drug and alcohol misuse in the six months before the start of the study. All subjects had the genotype of catechol-o-methyltransferase determined, and all took the Wisconsin test. The researchers found that people who had inherited two copies of the valine allelic variant performed worse on the Wisconsin test than those with only one valine. Those with two methionines performed best. Neuroimaging confirmed that subjects with two valines had less efficient functioning in their prefrontal cortex than those with methionine. BMJ 2001;322:1384 ( 9 June)
Diagnostic System Will Be Changed by Genetic Findings: The traditional dichotomous classification of the so-called "functional" psychoses form the basis of modern diagnostic practice in DSM-IV. However, genetic studies shows increasing evidence for an overlap in genetic susceptibility across the traditional classification categories--including association findings at DAOA(G72), DTNBP1 (dysbindin), COMT, BDNF, DISC1, and NRG1. For example, DISC1 and NRG1 may confer susceptibility to a form of illness with mixed features of schizophrenia and mania. Current findings highlight the need for alternative approaches to classification and conceptualization for psychiatric research rather than continuing to rely heavily on the traditional Kraepelinian dichotomy. Genes for Schizophrenia and Bipolar Disorder? Implications for Psychiatric Nosology. Craddock N, et al. Cardiff University. Schiz Bull 2005 Nov 30.
Dopamine Supersensitivity Recepter Gene RGH9-2: RGS9-2 gene knockout mice show supersensitivity to dopamine (DA) and have a marked elevation in the proportion of DA D2 receptors in the high-affinity state for DA. This is a similar profile to that observed in schizophrenia. In postmortem CNS tissue, researchers found reduced levels of RGS9-2 expression in both an animal model of schizophrenia and a postmortem schizophrenia brain. RGS9-2 ss a candidate gene in schizophrenia. Consistent with dopamine supersensitivity, RGS9 expression is diminished in the amphetamine-treated animal model of schizophrenia and in postmortem schizophrenia brain. Seeman P, et al. University of Toronto. Synapse 61:303-309, 2007.
DRP-2 Polymorphism Associated with Paranoid Schiz in Japan: . The human dihydropyrimidinase-related protein 2 gene on chromosome 8p21 is associated with paranoid-type schizophrenia. Nakata K, Ujike H, et al. Biol Psychiatry. 2003 Apr 1;53(7):571
DISC-1 Gene: Propose that DISC1(Disrupted-in-schizophrenia) is a multifunctional protein whose truncation contributes to schizophrenia susceptibility by disrupting intracellular transport, neurite architecture and/or neuronal migration, all of which have been hypothesized to be pathogenic in the schizophrenic brain. DISC1 (Disrupted-In-Schizophrenia 1) is a centrosome-associated protein that interacts with MAP1A, MIPT3, ATF4/5 and NUDEL: regulation and loss of interaction with mutation. Morris JA, Kandpal G, Ma L, Austin CP. Hum Mol Genet. 2003 Jul 1;12(13):1591-608.
DISC-1 Gene in Schizophrenia and Schizoaffective: In a large Scottish pedigree, a balanced translocation t(1;11)(q42.1;q14.3) segregates with major mental illness, including schizophrenia, bipolar disorder, and recurrent major depression. The translocation is predicted to result in the loss of the C-terminal region of the protein product of Disrupted In SChizophrenia 1 (DISC1), a gene located on 1q42.1. A 4 bp deletion at the extreme 3' end of exon 12 was found in one adult with schizophrenia. The mutation was also present in a sib with schizophrenia, a sib with schizoaffective disorder, and the unaffected father, while the mutation was not detected in 424 control individuals. The mutation is predicted to cause a frameshift and encode a truncated protein with nine abnormal C-terminal amino acids. The truncated transcript was detectable, but at a reduced level, in lymphoblastoid cell lines from three of four mutation carriers. These findings are consistent with the possibility that mutations in the DISC1 gene can increase the risk for schizophrenia and related disorders. A frameshift mutation in Disrupted in Schizophrenia 1 in an American family with schizophrenia and schizoaffective disorder. Sachs NA, et al. Johns Hopkins. Molecular Psychiatry, 10 May 2005.
DISC-1 Polymorphisms Affect Mitochondria and Hippocampus: Disrupted-in-schizophrenia 1 (DISC1) is expressed mainly in the hippocampus. Researchers typed 12 single-nucleotide polymorphisms (SNPs) that covered the DISC1 gene. A three-SNP haplotype [hCV219779 (C)-rs821597 (G)-rs821616 (A)] spanning 83 kb of the gene was associated with schizophrenia in a family-based sample (P = 0.002). A common nonconservative SNP (Ser704Cys) (rs821616) within this haplotype was associated with schizophrenia (P = 0.004). In addition to overtransmission in schizophrenia, the Ser allele was associated with altered hippocampal structure and function in healthy subjects, including reduced hippocampal gray matter volume and altered engagement of the hippocampus during several cognitive tasks assayed with functional magnetic resonance imaging. These convergent data suggest that allelic variation within DISC1, either at Ser704Cys or haplotypes monitored by it, increases the risk for schizophrenia and that the mechanism of this effect involves structural and functional alterations in the hippocampal formation. Variation in DISC1 affects hippocampal structure and function and increases risk for schizophrenia. Callicott JH, et al. National Institute of Mental Health, Bethesda, MD. Proc Natl Acad Sci U S A. 2005 Jun 14;102(24):8627-32; DISC1 over-expression produces striking mitochondrial reorganization in some cells, with formation of mitochondrial ring-like structures, indicating a potential involvement of DISC1 in mitochondrial fusion and/or fission. Mol Cell Neurosci. 2005 Oct 3
D3 Dopamine Receptor Polymorphism Respond More Poorly: Ser9Ser genotype of dopamine D3 receptor was more frequent in the nonresponder to atypicals subgroup (64%, p = 0.0018). The Ser9 allele was overrepresented among nonresponder patients (82%, p = 0.0172). Correlation between the effectiveness of atypical antipsychotics and dopamine D3 receptor polymorphism in schizophrenia. Szekeres G, Juhasz A, et al. Ideggyogy Sz. 2002 Nov 20;55(11-12):377-81
D5 Dopamine Receptor Gene Polymorphisms: polymorphism closely linked to D5 dopamine receptor gene with schizophrenia, but not bipolar or MDD. Muir, U Edinburgh, Am J Med Genet 2001 Mar 8;105(2):152-8
DRD2 Dopamine Receptor Gene Variant Predict Treatment Response: Previous reports have shown that both A1 allele carriers of TaqI A and Del allele non-carriers of -141C Ins/Del for dopamine D(2) receptor (DRD(2)) gene polymorphisms have a better antipsychotic drug response. In 49 acutely exacerbated inpatients with schizophrenia treated with bromperidol (30 cases, 6-18 mg/day) or nemonapride (19 cases, 18 mg/day) for 3 weeks, combined DRD(2) polymorphisms weakly predicted the response to DRD(2) antagonists (P = 0.049), that is, good response in A1(+) or Del(-) subjects and poor response in A1(-) plus Del(+) subjects. In the former subjects, non-responders with A1(+) or Del(-) showed higher scores of psychic, extrapyramidal and total side-effects. At therapeutic doses (6-8 mg/day haloperidol equivalent dose) in 30 subjects, the predictability of response was greatly increased (P < 0.0045) with higher positive and negative predictive values (78.3% and 85.7%, respectively). These findings suggest that combined DRD(2) polymorphisms can be used as a pretreatment marker for response to DRD(2) antagonists at therapeutic doses, and that A1(+) or Del(-) subjects are highly sensitive to DRD(2) antagonists, expressed as either treatment responders or non-responders vulnerable to extrapyramidal symptoms. Dopamine D(2) receptor gene polymorphisms predict well the response to dopamine antagonists at therapeutic dosages in patients with schizophrenia. Sakumoto N, et al. University of the Ryukyus, Okinawa, Japan. Psychiatry Clin Neurosci 2007 Apr;61(2):174-80.
DRD2 Dopamin Receptor Gene Variant Increases Schizophrenia: Dopamine D(2) receptor gene (DRD2) Ser311Cys variant and schizophrenia. In a replication attempt, Swedish patients with schizophrenia (n = 173) and control subjects (n = 236) were assessed for the DRD2 Ser311Cys variant. Schizophrenic patients displayed higher Cys311 allele frequencies than control subjects (4.0 vs. 0.8%, chi(2) = 9.49, df = 1, P = 0.002; odds ratio (OR) 4.93. Karolinska. Dopamine D2 receptor gene Ser311Cys variant and schizophrenia: association study and meta-analysis. Jonsson EG, Sillen A, Vares M, Ekholm B, Terenius L, Sedvall GC. Am J Med Genet. 2003 May 15;119B(1):28-34
DRD2 Polymorphism Associated with Schizophrenia in India: In a case-control study with 101 cases of schizophrenia and 145 controls, genotype distribution for the SNP His313 polymorphism in DRD2 was significantly different between schizophrenia patients and control subjects (p=0.0012), but not the Pro319 polymorphism. Association of DRD2 gene variant with schizophrenia. Kukreti R, et al. Delhi, India. Neurosci Lett. 2005 Sep 21
Dysbindin-1 Polymorphisms Repeatedly Linked to Negative-Symptom Schizophrenia: First reported by Straub et al, who undertook association mapping across the linkage region on chromosome 6p22.3, significant associations have been found between schizophrenia and several SNPs and multimarker haplotypes spanning DTNBP1. A second study based on 203 families, most of which came from Germany, provided further evidence for association between DTNBP1 and schizophrenia as did 2 large studies from Cardiff University, which included approximately 900 schizophrenic patients from the United Kingdom and Ireland and 488 parent-proband trios from Bulgaria. Although there have also been some studies in which no association was found, significant associations in a total of 10 samples have now been published. Dysbindin 1 binds both - and ß-dystrobrevin, which are components of the dystrophin glycoprotein complex. The dystrophin complex is found in the sarcolemma of muscle but is also located in postsynaptic densities in a number of brain areas, particularly mossy fiber synaptic terminals in the cerebellum and hippocampus. Although its functions are largely unknown, its location initially suggested that variation in DTNBP1 might confer risk of schizophrenia by mediating effects on postsynaptic structure and function. However, Talbot et al have recently shown that the presynaptic dystrobrevin-independent fraction of dysbindin is reduced in the schizophrenic brain within certain intrinsic glutamatergic neurones of the hippocampus and that this is associated with increased expression of vesicular glutamate transporter type 1. Moreover, a reduction in glutamate release has been demonstrated in cultured neurons with reduced DTNBP1 expression. J Clin Invest. 2005 Jun;115(6):1440-8; A particular polymorphism was most strongly linked to schizophrenia with high negative symptoms. Am J Psychiatry. 2005 Oct;162(10):1824-32
Epsin 4 Gene Enthoprotin Abnormality a Cause of Schizophrenia: Chromosome 5q33 is a region that has previously shown good evidence of linkage to schizophrenia. In a study of 450 unrelated patients with schizophrenia and 450 ancestrally matched supernormal controls, four adjacent markers at the 5' end of the Epsin 4 gene showed significant linkage with schizophrenia: two microsatellite markers, D5S1403 (P=.01) and AAAT11 (P=.009), and two single-nucleotide-polymorphism markers within the Epsin 4 gene, rs10046055 (P=.007) and rs254664 (P=.01). Haplotypes were also significantly associated with schizophrenia (HapA, P=.004; HapB, P=.0005; HapC, P=.007; and HapD, P=.01). The Epsin 4 gene encodes the clathrin-associated protein enthoprotin, which has a role in transport and stability of neurotransmitter vesicles at the synapses and within neurons. Pimm J, McQuillin A, et al. University College London Medical School, UK. Am J Hum Genet. 2005 May;76(5):902-7.
Folate MTHFR Gene C677T Polymorphism Increases Risk Via Disturbed Homocysteine Metabolism: The 677C>T polymorphism in the methylenetetrahydrofolate reductase (MTHFR) gene results in reduced enzyme activity and, subsequently, in elevated homocysteine, which has been found elevated in some schizophrenia studies. A meta-analysis of eight retrospective studies (812 cases and 2113 control subjects) to examine the association between homocysteine and schizophrenia and a meta-analysis of 10 studies (2265 cases and 2721 control subjects) on the homozygous (TT) genotype of the MTHFR 677C>T polymorphism found that a 5 mumol/l higher homocysteine level was associated with a 70% higher risk of schizophrenia. The TT genotype was associated with a 36% higher risk of schizophrenia compared to the CC genotype. A disturbed homocysteine metabolism causes an increased risk of schizophrenia. Homocysteine, methylenetetrahydrofolate reductase and risk of schizophrenia: a meta-analysis. Muntjewerff JW, et al. Nijmegen, The Netherlands. Molecular Psychiatry 20 September 2005.
Folate MTHFR Gene C677T Polymorphism Increases Risk A Little: The MTHFR gene C677T polymorphism influences folate metabolism and intracellular availability of folate metabolites for methylation. A meta-analysis of MTHFR C677T genotype and schizophrenia risk found that TT homozygotes had a significantly increased risk, OR 1.48 (1.18-1.86). This supports the hypothesis that folate status is a determinant of schizophrenia risk. A meta-analysis of the MTHFR C677T polymorphism and schizophrenia risk. Lewis SJ, Zammit S, et al. University of Bristol, United Kingdom. Ed: More evidence of the wisdom of taking a folic acid supplement.
Folate MTHFR Gene T677T, A1298A, C677C, C1298C Polymorphisms Increase Risk: The researchers previously found an association between the methylenetetrahydrofolate reductase (MTHFR) gene C677T and A1298C polymorphisms and schizophrenia in patients from Bakirkoy, Turkey [Sazci, A., et al. Mol. Brain Res. 117, 104-107]. To confirm this, they analyzed the genotypes of MTHFR677 and MTHFR1298 of 297 schizophrenic patients and 341 healthy controls from Erenkoy, Turkey. The T677T genotype was overrepresented in the total schizophrenic patients (OR=1.94; P=0.014). Similarly, the T677T/A1298A compound genotype was the most significant one in the total schizophrenic patients (OR=2.40; P=0.003). The C1298C genotype was overrepresented in the total schizophrenic patients (OR=1.71; P=0.042). Likewise, the C677C/C1298C compound genotype was significant in the total schizophrenic patients (OR=1.69; P=0.055). The T677T genotype and T677T/A1298A compound genotype were significantly overrepresented (OR=2.18; P=0.029; OR=2.75; P=0.012) in men schizophrenic patients, but not women. Association of the C677T and A1298C polymorphisms of methylenetetrahydrofolate reductase gene with schizophrenia: Association is significant in men but not in women. Sazci A, et al. University of Kocaeli, Kocaeli, Turkey. Prog Neuropsychopharmacol Biol Psychiatry. 2005 Aug 2
FOXP2 Gene Polymorphism Associated with Hallucinations: A mutation in the FOXP2 gene has been associated with a language disorder. Language disorder is considered as a core symptom of schizophrenia. In 186 DSM-IV schizophrenic patients with auditory hallucinations and in 160 healthy controls, differences in the genotype (P=0.007) and allele frequencies (P=0.0027) between schizophrenic patients with auditory hallucinations and controls were found in the single nucleotide polymorphism rs2396753. rs7803667T/rs10447760C/ rs923875A/rs1358278A/rs2396753A (TCAAA) also showed a difference (P=0.009). Association between FOXP2 polymorphisms and schizophrenia with auditory hallucinations. Sanjuan J, et al. University of Valencia, Spain. Psychiatr Gen 2006 Apr;16(2):67-72.
G72, a 2nd NMDA Receptor Activity Gene Thought Linked to Schizophrenia: Increased tendency was found in 200 schizophrenic patients in Quebec and 200 in Moscow on chromosome 13. G72 was found by identifying sequences appearing more often in schizophrenia. Then, the sequence was cloned and produced a protein interacting with D-amino acid oxidase (DAAO) which lowers NMDA receptor reception of glutamate. It's primate specific. French Daniel Cohen, Proceedings Natl Acad Sci 10/02.
GABA Receptor Genes of 5q Linked to Schizophrenia: A genome-wide linkage scan in Portuguese schizophrenia families that identified a risk locus on chromosome 5q31-q35. A meta-analysis of 20 other schizophrenia genome-wide scans that identified 5q23.2-q34 as the second most compelling susceptibility locus. A study of the group of gamma-aminobutyric acid (GABA) A receptor subunit genes (GABRA1, GABRA6, GABRB2, GABRG2, and GABRP) found associations in a Portuguese patient sample with single nucleotide polymorphisms (SNPs) and haplotypes in GABRA1 (P=0.00062-0.048), GABRP (P=0.0024-0.042), and GABRA6 (P=0.0065-0.0088). The GABRA1 and GABRP findings were replicated in the second stage in an independent German family-based sample (P=0.0015-0.043). Supportive evidence for association was also obtained for a previously reported GABRB2 risk haplotype. Exploratory analyses of the effects of associated GABRA1 haplotypes on transcript levels found altered expression of GABRA6 and coexpressed genes of GABRA1 and GABRB2. Comparison of transcript levels in schizophrenia patients and unaffected siblings found lower patient expression of GABRA6 and coexpressed genes of GABRA1. The GABRA1 coexpressed genes include synaptic and vesicle-associated genes previously found altered in schizophrenia prefrontal cortex. Genetic investigation of chromosome 5q GABA(A) receptor subunit genes in schizophrenia. Petryshen TL, et al. Harvard and MIT. Molecular Psychiatry 20 September 2005
Genome Scan Suggests No Single Gene Cause Large Amount: 269 individuals including 126 schizophrenics were assessed by nonparametric linkage analysis. Other studies suggest 65-85% susceptibility can be attributed to genes. A total of 43 pedigrees were studied with 2-4 affected individuals per family. Levinson, Allegheny U, Am J Psychiatry 155:741-50
GRIN1 NMDA Receptor Polymorphism Involved: Of two NMDA receptor subunit genes, GRIN1 and GRIN2A in 2455 Han Chinese subjects, a highly significant association was detected at the 5' end of GRIN1. Analyses of single variants and multiple-locus haplotypes indicate that the association is mainly generated by rs11146020 (case-control study: p = .0000013). No association was found in the GRIN2A polymorphisms. Significant Association Between the Genetic Variations in the 5' End of the N-Methyl-D-Aspartate Receptor Subunit Gene GRIN1 and Schizophrenia. Zhao X, et al. Shanghai Jiao Tong University. Biol Psychiatry 2006 Feb 11.
GRIN 2A Repeat of NMDA Glutamate Receptor Subunit Increases Risk of Schizophrenia: Dysfunction of the N-methyl-d-aspartate (NMDA) type glutamate receptor has been proposed as a mechanism in the etiology of schizophrenia. In a large case-control study of 672 schizophrenics and 686 controls, there was an allelic association between the repeat polymorphism and the disease (P=0.011) with an over-representation of longer alleles in schizophrenia. Extended analyses support the association of a functional (GT)(n) polymorphism in the GRIN2A promoter with Japanese schizophrenia. Iwayama-Shigeno Y, et al. RIKEN Brain Science Institute, Saitama, Japan. Neurosci Lett. 2005 Apr 18;378(2):102-5.
HOPA X-Chromosome Disequilibrium: The balanced uncommon polymorphism HOPA is the defining polymorphism for a large X-chromosome haplotype in population disequilibrium and that it is associated with a positive syndrome of psychosis in multiple studies for both men and women. A meta-analysis of the association of the HOPA12bp polymorphism and schizophrenia. Philibert RA. University of Iowa. Psychiatric Genetics 2006 Apr;16(2):73-6.
Interleukin-1 Receptor Antagonist Gene Polymorphism Linked to Ventricular Enlargement in Schizophrenia: In an MRI study of 23 DSM-IV diagnosed schizophrenic patients vs. a healthy control group (n = 45), patients carrying VNTR-allele*2 of IL-1RN gene showed a significant enlargement of both left (P = 0.002) and right (P = 0.01) ventricles. Ventricular enlargement in schizophrenia is associated with a genetic polymorphism at the interleukin-1 receptor antagonist gene. Papiol S, et al. Universitat de Barcelona, Spain. Neuroimage. 2005 Jul 11
IL-10 Gene Abnormality Linked: IL-10 gene maps on chromosome 1 (q31-q32), a locus associated with genetic susceptibility to schizophrenia. Study of 106 schiz and 143 controls found GCC pattern more often in schiz OR=3.03. abnormal secretion of IL-10 occurring in schizophrenic patients in response to infections or different stressors and suggest a potential role of IL-10 as a candidate gene for susceptibility to schizophrenia. Biol Psychiatry 2002 Mar 15;51(6):480-4, Breschiz, Italy; A Polish study of 24 schiz found increased serum levels of some cytokines such as IL-6, IL-8 and IFN-gamma indicate an activation of the inflammatory response in schizophrenia. IL-10 was decreased. Arch Immunol Ther Exp (Warsz) 2001;49(6):439-45
IL-10 Not Linked in Korea: Psychiatry Clin Neurosci. 2003 Apr;57(2):153-9.
Karyopherin Genes Linked: Recent studies suggest that both the KPNB3 gene and the KPNA3 gene in the long arm of chromosome 13 (13q) are associated with schizophrenia. In 238 Chinese family trios consisting of fathers, mothers and affected offspring with schizophrenia, the combination of the KPNA3 gene and the KPNB3 gene was linked to an increase a genetic risk for schizophrenia. Neurosci Lett 2006 Apr 24.
Microtubular Gene Might be Linked: Pathologic lesions of schizophrenia may in part be due to the altered cytoskeletal architecture of neurons. Microtubule-associated proteins (MAPs) that bind to cytoskeletal microtubules to stabilize their assembly are prominently expressed in neurons. Mice deficient in MAP6 display neuroleptic-responsive behavioral defects. In 570 schizophrenics vs. 570 controls, single nucleotide polymorphism (SNP) markers detected nominal allelic (p=0.0291) and haplotypic (global p=0.0343 for 2 SNP-window, global p=0.0138 for 3 SNP-window) associations between the 3' genomic interval of the gene and schizophrenia. A postmortem brain expression study showed up-regulation of mRNA isoform 2 in the prefrontal cortex (Brodmann's area 46) of patients with schizophrenia. Genetic and expression analyses of the STOP (MAP6) gene in schizophrenia. Shimizu H, et al. RIKEN Brain Science Institute, Japan. Schiz Res 2006 Apr 17.
Multiple Copies Cause Some Schizophrenia, Bipolar, Early-Onset Alzheimers, and Charcot-Marie-Tooth Disease: Literally everyone inherits genetics duplications or deletions covering entire genes with one study finding 11 in the average person. Duplications or deletions covering less than an entire gene are even more common and as genetic tools improve, variation appears even more frequent. Charcot-Maorie-Tooth syndrome, a common hereditary disease affecting the nervous system, is entirely due to having an extra copy of one section of chromosome 17. Genetic deletions cause the Rh negative blood types and some forms of color blindness. New Scientist 4/8/06.
Myelin-Associated Glycoprotein Gene Polymorphisms Linked to Schizophrenia: Results of gene expression microarray and quantitative PCR studies have suggested abnormalities in the expression of myelin-related genes including myelin-associated glycoprotein (MAG) in schizophrenic patients. Research provides strong evidence for oligodendrocyte dysfunction in schizophrenics. In this study of four single nucleotide polymorphisms (SNPs), rs2301600, rs3746248, rs720309 and rs720308, of this gene in Chinese schizophrenic patients (n=470) and healthy controls (n=470). The distribution of rs720309 T/A genotypes showed a strong association with schizophrenia (P=0.0008). A haplotype constructed of rs720309-rs720308 also revealed a significant association with schizophrenia (P=0.0084). Polymorphisms of myelin-associated glycoprotein gene are associated with schizophrenia in the Chinese Han population. Wan C, et al. Center for Human and Animal Genetics, Beijing, China; Shanghai Jiao Tong University. Neurosci Lett. 2005 Jul 19
Neurogranin Polymorphism Linked: Another Glutaminergic Gene: The neurogranin (NRGN) gene produces a postsynaptic brain-specific protein that regulates calmodulin-Ca(2+) availability in neurons. Acting downstream of the NMDA receptor and upstream of calcineurin and other proteins implicated in schizophrenia, NRGN expression is regulated during development and is modulated by thyroid hormones and retinoids, molecules essential for the proper development of the central nervous system. In 73 Azorean proband-parent schizophrenic triads and in two independent case-control samples from the Portuguese-mainland (244 schizophrenic and 210 controls) and Brazil (69 schizophrenic and 85 mentally healthy individuals), genotype distribution showed association of the rs7113041 SNP with schizophrenia in males of Portuguese origin, which was confirmed by the analysis of the proband-parent triads. NRGN may be another player into the glutamatergic hypothesis of schizophrenia. Association of the gene encoding neurogranin with schizophrenia in males. Ruano D, et al. University of Minho, Braga, Portugal. J Psychiatr Res 2006 Nov 29.
Neuregulin-1 on Chromosome 8, Dysbindin. Mutations in the gene are highly correlated with schizophrenia in about 15 percent of Icelandic patients. 270 Irish families, each with several schizophrenic members, (Virginia Commonwealth University) gene dysbindin and lies on the sixth chromosome also implicated. Dysbindin, the gene identified by the Richmond group, is involved in the operation of the synapses. Genetic variations in the dysbindin gene all in introns, the spacer regions of the DNA that lie between the working parts of the dysbindin gene. Kendler. NYT 7/4/02. Strong evidence for association with the same haplotype was subsequently found in a large sample from Scotland and weakly replicated in a United Kingdom sample. Further positive findings have emerged from Irish, Chinese, and South African samples. However, some negative findings have also been reported. Only the 3 studies of Icelandic, Scottish, and UK samples have implicated the specific Icelandic haplotype. Neuregulin encodes for 15 proteins with brain functions. J. Clin. Invest. 115:1440-1448 (2005).
Neuregulin-1 Polymorphisms Linked to Late Onset Alzheimer's with Psychosis: Probands with late onset Alzheimer's disease (LOAD) exhibit positive symptoms of psychosis, 30-60% of the time. Positive symptoms of psychosis have been shown to appear prior to the onset of dementia to be accompanied by greater cognitive deficits, and to predict a more rapid decline. A study of the distribution of AD with psychosis (ADP) in families from the NIMH Alzheimer's Disease Genetic Initiative sample indicates that the trait is heritable, and linkage studies of multiplex ADP families have found suggestive peaks on 2p, 6q, 8p, and 21q. A genome scan of idiopathic psychosis, schizophrenia, in the Icelandic population identified a risk haplotype within the 5' region of neuregulin-1 (NRG1) on 8p12. Associations with NRG1 SNPs have also been found in other schizophrenia populations from Scotland, Ireland, and China. Here, researchers found a significant linkage peak for ADP on 8p12 in the NIMH AD dataset, encompassing the NRG1 region. The NRG1 SNP (single nucleotide polymorphism), rs392499, was linked with ADP, P = 0.008. This same SNP is part of a 3-SNP haplotype preferentially transmitted to individuals with this phenotype. NRG1 plays a role in increasing the genetic risk to positive symptoms of psychosis in a proportion of LOAD families. Neuregulin-1 polymorphism in late onset Alzheimer's disease families with psychoses. Go RC, et al. University of Alabama, Birmingham, Alabama. Am J Med Genet B Neuropsychiatr Genet. 2005 Aug 4
Nicotinic Receptor Alpha-7 Dysfunction Involved: Freedman's group was able to show that a relatively common genetic mutation in nicotinic receptors, found in 10% of the population, caused difficulties in sensory gating and could be a predisposing factor for the impaired cognition and psychosis seen in schizophrenia. His research indicates a deficit in inhibitory interneuronal function, involving the alpha7-nicotinic receptor, as an integral feature of the altered neurocircuitry in schizophrenia. Such impaired nicotinic receptor function could be at the heart of the dramatically increased use of nicotine in patients with schizophrenia. Freedman R. Nicotinic receptors and the genetics of schizophrenia and bipolar disorder. Program and abstracts of the American Psychiatric Association 155th Annual Meeting; May 18-23, 2002; Philadelphia, Pennsylvania. Industry-supported Symposium No. 24B.
Nogo Gene Variant Homozygotes Increased Risk: Nogo gene involved in inhibiting growth of nerve endings in brain and over-active in post-mortem schizophrenic brain. Gene variant increases gene activity by three extra CAA base variation in area of gene that regulates protein production. 21% of schiz but only 3% normals inherit abnormal copy from both parents. Present globally. U Toronto, Molecular Brain Research 11/15/02
PAS3 Gene Defect in One Family: University of Alberta studied a British mother and daughter found to have a "break" in a large gene on human chromosome 14, due to a rearranged chromosome. The broken gene is a member of a family of similar genes affecting brain development and function. The genes in this group are involved in behaviour, memory and regulating day/night cycles. Diane Cox, Deepak Kamnasaran, May ’03, J Medical Genetics, "Disruption of the neuronal PAS3 gene in a family affected with schizophrenia."
PDLIM5 Polymorphisms May be Involved Via Nuclear Binding: DNA microarray analyses of postmortem brains of patients with schizophrenia reveal that expression of the PDZ and LIM domain 5 gene (PDLIM5) is increased. Researchers found mutations in PDLIM5 in 24 Japanese patients out of 278 schizophrenia patients and 462 control subjects. Expression of PDLIM5 was quantified by real-time quantitative polymerase chain reaction (PCR) in postmortem prefrontal cortex of 34 schizophrenia patients. There were 27 polymorphisms in PDLIM5 and associations between polymorphisms (rs2433320 and rs2433322) in the 5' region of the gene and schizophrenia (p = .004). Real-time quantitative PCR revealed that these polymorphisms influenced gene expression (p = .007). An EMSA showed that the different alleles of the rs2433320 polymorphism bound differently to nuclear proteins. A Polymorphism in the PDLIM5 Gene Associated with Gene Expression and Schizophrenia. Horiuchi Y, et al. University of Tsukuba, Saitama, Japan. Biol Psychiatry. 2005 Oct 4
PDE4B Gene Defects Involved with DISC1: Phosphodiesterase 4B (PDE4B) is involved in brain development and memory storage. Damage to it can increase the risk of a mental health problem. The PDE4B protein and the DICS1 protein interact with each other. University of Edinburgh, BBC News 11/18/05.
Phosphohippolin Gene Variants Linked to Schizophrenia in Two Huge Studies: Previous linkage analyses of families with multiple cases of schizophrenia have confirmed the involvement of the chromosome 11q22-24 region in schizophrenia. In a new study of fine mapping of a susceptibility gene in the 11q22-24 region in 496 London schizophrenic patients and 488 supernormal controls was confirmed by a second study of 858 Aberdeen patients and 591. Seven microsatellite or single-nucleotide polymorphism ( SNP ) markers localized within or near the FXYD6 gene showed significant associations with schizophrenia in the UCL sample (for D11S1998, P=.021; for rs3168238, P=.009; for TTTC20.2, P=.048; for rs1815774, P=.049; for rs4938445, P=.010; for rs4938446, P=.025; for rs497768, P=.023). Several haplotypes were also found to be associated with schizophrenia; for example, haplotype Hap-F21 comprising markers rs10790212-rs4938445-rs497768 was found to be associated with schizophrenia (P=.002). Positive markers in the UCL sample were then genotyped in the Aberdeen sample. Two of these SNPs were found to be associated with schizophrenia in the Scottish sample (for rs4938445, P=.044; for rs497768, P=.037). The Hap-F21 haplotype also showed significant association with schizophrenia in the Aberdeen sample, with the same alleles being associated (P=.013). The FXYD6 gene encodes a protein called "phosphohippolin" that is highly expressed in regions of the brain thought to be involved in schizophrenia. The protein functions by modulating the kinetic properties of Na,K-ATPase to the specific physiological requirements of the tissue. A Genetic Association Study of Chromosome 11q22-24 in Two Different Samples Implicates the FXYD6 Gene, Encoding Phosphohippolin, in Susceptibility to Schizophrenia. Choudhury K, et alUniversity College London Medical School , UK . Am J Human Genetics 2007 Apr;80(4):664-72.
PLXNA2 Gene Variant of Transmembrane Semaphor Family for Axonal Guidance Involved: A gene on chromosome 1q32, plexin A2 (PLXNA2), in a genome-wide association study using 320 patients with schizophrenia of European descent and 325 controls. Over 25 000 single-nucleotide polymorphisms (SNPs) located within approximately 14 000 genes were tested. Out of 62 markers found to be associated with schizophrenia, the most consistent finding was observed for a candidate locus on chromosome 1q32. The marker SNP rs752016 showed suggestive association with schizophrenia (odds ratio (OR)=1.49, P=0.006). This result was confirmed in an independent case-control sample of European Americans (OR=1.38, P=0.035) and similar genetic effects were observed in smaller subsets of Latin Americans (OR=1.26) and Asian Americans (OR=1.37). Supporting evidence was also obtained from two family-based collections, one of which reached statistical significance (OR=2.2, P=0.02). High-density SNP mapping showed that the region of association spans approximately 60 kb of the PLXNA2 gene. Eight out of 14 SNPs genotyped showed statistically significant differences between cases and controls. PLXNA2 is a member of the transmembrane semaphorin receptor family that is involved in axonal guidance during development and may modulate neuronal plasticity and regeneration. The PLXNA2 ligand semaphorin 3A has been shown to be upregulated in the cerebellum of individuals with schizophrenia. Identification of the semaphorin receptor PLXNA2 as a candidate for susceptibility to schizophrenia. Mah S, et al. San Diego. Molecular Psychiatry. 10 January 2006.
PPP 3CC Gene Defects Linked to Some Cases of Schizophrenia: Calcineurin is a calcium/calmodulin-dependent protein phosphatase composed of two subunits, a regulatory subunit of calcineurin B ( CNB ) and a catalytic subunit of calcineurin A ( CNA ). PPP 3CC is the gamma isoform of CNA located at the chromosome 8p21.3 region. This study suggests that PPP 3CC gene may be a true susceptibility gene for schizophrenia with increased frequency of disease found in patients with various polymorphisms. More evidence supports the association of PPP 3CC with schizophrenia. Liu YL, et al. National Health Research Institutes, Taipei , Taiwan.Molecular Psychiatry, 6 March 2007
Proline Dehydrogenase Gene Polymorphism in Some: proline dehydrogenase gene (PRODH), located in the most centromeric part of the 22q11 microdeletion region, has been reported to be strongly associated with schizophrenia from three sets of independent samples and the most significant evidence for association was derived from a single nucleotide polymorphism-PRODH*1945(T/C). We genotyped this polymorphism in 166 Chinese family trios with schizophrenia from East China. No evidence in this study. Neurosci Lett 2003 Mar 6;338(3):252-4
QK1 Gene Variant May Cause Some Schizophrenia by Interfering with Myelination and Nerve Development: Chromosome 6q25-6q27 includes a susceptibility locus for schizophrenia in a large pedigree from northern Sweden. A 0.5 Mb haplotype, likely to be inherited identical by decent, within the large family that is shared among the majority of the patients (69%) was found. A gamete competition test of this haplotype in 176 unrelated nuclear families from the same geographical area as the large family showed association to schizophrenia (empirical P-value 0.041). The only gene located in the region, the quaking homolog, KH domain RNA binding (mouse) (QKI), was investigated in human brain autopsies from 55 cases and 55 controls using a high-resolution mRNA expression analysis. Relative mRNA expression levels of two QKI splice variants were clearly downregulated in schizophrenic patients (P-value 0.0004 and 0.03, respectively). The mouse homolog is involved in neural development and myelination. Human QKI, a new candidate gene for schizophrenia involved in myelination. Aberg K, et al. Uppsala University, Sweden. Am J Med Gen 2006 Jan 5;141(1):84-90.
Rett Syndrome MECP2 Gene Causes Some Schiz: MECP2 was mutated in the Rett Syndrome girls, a cause in retardation in 1/10,000. Earlier research suggested that the MeCP2 protein was responsible for making sure that genes the cell has marked with a molecular tag, called a methyl group, are silenced. The MeCP2 protein latches on to these methyl groups and prevents them from being translated into protein. cases of classic autism and schizophrenia that are caused by mutations in this gene. Neuron 7/18/02
RGS4 Regulator of G-Protein Signaling 4: transcript encoding regulator of G-protein signaling 4 (RGS4) was the most consistently and significantly decreased in the prefrontal cortex of all schizophrenic subjects examined. The expression levels of ten other RGS family members represented on the microarrays were unchanged and hierarchical data analysis revealed that as a group, 274 genes associated with G-protein signaling were unchanged. Quantitative in situ hybridization verified the microarray RGS4 data, and demonstrated highly correlated decreases in RGS4 expression across three cortical areas of ten subjects with schizophrenia. RGS4 expression was not altered in the prefrontal cortex of subjects with major depressive disorder or in monkeys treated chronically with haloperidol. Interestingly, targets for 70 genes mapped to the major schizophrenia susceptibility locus 1q21--22 were present on the microarrays, of which only RGS4 gene expression was consistently altered. Mirnics, U Pittsburgh, Mol Psychiatry 2001 May;6(3):293-301; Studies show polymorphisms of RGS4 more common in schizophrenia. Similar in review of 10 studies. Biol Psychiatry 2006 Apr 19
Serotonin Transporter Gene STin2 VNTR Polymorphism: Meta-analysis reveals association between serotonin transporter gene STin2 VNTR polymorphism and schizophrenia. Fan JB, et al. MGH-Harvard. Mol Psychiatry. 2005 Oct;10(10):891.
Synapsin III Gene Polymorphism in African Americans: Linkage studies in families with schizophrenia have pointed to chromosome 22q12-q13 as one of several regions of the genome that may contain a susceptibility gene. The gene coding for synapsin III, an intrinsic synaptic vesicle membrane protein, maps to this target region. Two tightly linked single-nucleotide polymorphisms were recently found in a small subset of patients with schizophrenia - a synonymous variant, L469L (469G>A), and a non-synonymous variant, S470N (470G>A) - which results in the loss of a mitogen-activated protein kinase serine phosphorylation site. Both single-nucleotide polymorphisms were much more polymorphic in African-American controls than in European-American controls, thereby providing a better sample cohort to analyze for schizophrenia involvement. For the codon 469 single-nucleotide polymorphisms, a 50-fold increase was observed in the frequency of 469A in African Americans compared with Caucasians. Furthermore, there was an increase in the percentage of African American patients with schizophrenia who were homozygous for the 469A allele compared with controls who were homozygous (11 versus 5%; AA vs. all other genotypes - P=0.04). An increase in 470A heterozygotes was also found, but the results fell short of being statistically significant. Association of schizophrenia in African Americans to polymorphism in synapsin III gene. Lachman HM, Stopkova P, et al. Albert Einstein, Bronx, New York. Psychiatr Genet. 2005 Jun;15(2):127-32.
Synapsin2 and Complexin2 Gene Polymorphism Linked in Koreans: Previous studies have reported that the protein and mRNA levels of the synapsin 2 (SYN2) and complexin 2 (CPLX2) genes were decreased in patients with schizophrenia. Synapsin 2 and complexin 2 are involved in synaptogenesis and the modulation of neurotransmitter release. Six single nucleotide polymorphisms (SNPs) and one 5-bp insertion/deletion in SYN2 and five SNPs in CPLX2 were genotyped in 154 Korean patients with schizophrenia and 133 controls. Although there was no significant difference in the genotypic distributions and allelic frequencies of either SYN2 or CPLX2 polymorphisms, the two-way haplotype analyses revealed significant associations with the disease (P < 0.05). The three-way haplotype analyses also revealed a significant association of SYN2 with schizophrenia (P < 0.001). Association Study of polymorphisms in synaptic vesicle-associated genes, SYN2 and CPLX2, with schizophrenia. Lee HJ, et al. Behav Brain Funct. 2005 Aug 31;1(1):15
TBP/SCA17 Trinucleotide Repeats More Common in Schizophrenia: Trinucleotide repeat (TNR)-containing TBP/SCA17 genes were found more often 100 unrelated schizophrenia patients than in 124 controls without evident neurodegenerative or psychiatric disorders (P=0.0149), with an increased frequency of 36 repeats in the patients and two patients carrying 45 TNR expansions were identified. TBP/SCA17 is the TATA box binding protein gene mapped to chromosome 6q27. TNR expansions of the TBP/SCA17 gene may contribute to the genetic risk of schizophrenia in a small percentage of cases. Expanded trinucleotide repeats in the TBP/SCA17 gene mapped to chromosome 6q27 are associated with schizophrenia. Lee-Chen GJ, et al. National Taiwan Normal University. Schizophr Res. 2005 Jul 28
Trace Amine Associated Receptor 6 Polymorphisms in Korean Patients: TAAR6 gene polymorphisms were measured in a case control sample of 281 schizophrenics, 190 bipolars, 187 major depressives and 288 controls. Five single nucleotide polymorphisms (SNPs: rs4305745; rs8192625; rs7452939; rs6903874 and rs6937506) were genotyped in the TAAR6 gene and in the 3' regulatory region, using pyrosequencing. SNP rs6903874 was significantly associated with schizophrenia (p=0.012) and bipolar disorder (p=0.004). A three SNP haplotype consisting of alleles GCT from SNPs rs7452939, rs6903874 and rs6937506, respectively, was significantly over-represented in patients with schizophrenia (p=0.0003) and bipolar disorder (p=0.00002). A second three SNP haplotype (GTT) derived from the same SNPs was significantly under-represented in patients with bipolar disorder (p=0.001). The GTT haplotype associations withstand the most rigorous corrections for multiple testing. These findings strongly support association of the TAAR6 gene with susceptibility to both schizophrenia and bipolar disorder in Korean patients. Association of the trace amine associated receptor 6 (TAAR6) gene with schizophrenia and bipolar disorder in a Korean case control sample. Pae CU, et al. Catholic University of Korea, Seoul;, Duke University. J Psychiatr Res 2006 Nov 8.
Tumor Necrosis Factor Allele Maybe up in Schizophrenia: Frequency of the TNF2(A) allele is significantly increased in schizophrenic patients as compared to controls (P = 0.0042). Genotype distribution is also significantly different (P = 0.0024). TNF2 homozygotes are represented only in the patient group (P = 0.002). Breschia, Italy. 84 schiz 138 controls. Could cause disregulation of immune system that has been found in some schiz.; U Iowa study didn’t find any connection to schiz susceptibility. Mol Psychiatry 2000 Nov;5(6):678-82
Velo-Cardio-Facial Syndrome 22q11 Deletion: Aside from being the child of two parents with schizophrenia or the monozygotic co-twin of an affected individual, VCFS and deletion 22q11 represents the highest known risk factor for the development of schizophrenia. Lancet 2002 Feb 2;359(9304):426-30
Velo-Cardio-Facial Syndrome Cause of Schiz: Lancet 2/2/02 VCFS most frequent interstitial deletion known. Microdeletions in q11 band of chromosome 22. High rate psych diff, esp schiz. Face variable with small downturned mouth, prominent nose, narrow palpebral fissures, flattened malar eminences, and long face. 1/4000 births. 30% of VCFS patients develop psychosis. Researchers estimate VCFS abnormalities account for 2-6% of schizophrenia, i.e., with 22q11 deletions.
Velocardiofacial Syndrome: 1 in 4000 births caused by a 22q11 microdeletion in the long arm of chromosome 22; 78%-90% are de novo with the rest inherited. Facies has a hypoplastic alae nasae with a bulbous tip and prominent root, There is a long, narrow face with flat cheeks, narrow palpebral fissures, small mouth, receeded chin, and small, cupped ears. Heart abnormalities are present in 75%, most commonly tetralogy of Fallot. Cleft palate or velopharyngeal incompetence occur in 80%. IQ ranges from moderate retarded to normal with a borderline MR average. 25% become schizophrenic with depression and anxiety also higher. ADHD is present in 40% as inattentive or combined types only and 25% oppositional disorder but no conduct disorder.
Thomas E. Radecki, M.D., J.D.