Schizophrenia

13q32 [HGL]
    A schizophrenia susceptibility locus has been mapped to chromosome 13q32.  Statistical analysis of tissue samples from twenty-one different families identified a DNA marker at 13q32 was linked to the occurrence of schizophrenia.  The linkage-marker showed a recessive mode of inheritance.  Brzustowicz et al., Am. J. Hum. Genet., 65:1096-1103, 1999.

Xp22.3 [HGL]
    Two unrelated patients with schizophrenia had a chromosomal deletion in chromosome Xp22.3, suggesting that this region contains a gene involved in the pathogenesis of paranoid schizophrenia.  Milunsky et al., Clin. Genet., 55:455-460, 1999.

brain derived neurotrophic factor (BDNF) [HGL]
    Brain derived neurotrophic factor is involved in the development of the dopaminergic system and in the maintainence of dopamine DR3 expression.  BDNF has also been shown to directly modulate membrane potential by activating sodium channels via the Trk receptor, a receptor to which BDNF binds.  See, e.g., Kafitz et al., Nature, 401:918-921, 1999.  Various dinucleotide polymorphisms in exon 1 of human BDNF have been identified.  There were no significant differences in the distribution of these polymorphisms between normal and schizophrenic patients as a group.  However, when schizophrenics were subdivided based on clinical feartures, significant differences were observed between the subgroups.  Patients with late onset schizophrenia had an excess of the long-allele polypmorphisms as compared with patients with an age of onset before 25 years.  Treatment-responding patients also had an excess of the long-allele polymorphisms as compared to schizophrenics who were refractory to treatment.  Krebs et al., Mol. Psychiatry, 5:558-562, 2000.

calcium-activated potassium channel, hKCa3 + [HGL]
    Schizophrenic patients had a higher frequency of alleles with greater than 19 CAG repeats in the hKCa3 gene than controls.  Bowen et al., Mol. Psychiatry, 3:266-269, 1998.  Long CAG repeats were asssociated with higher negative symptom dimension score, but not gender, age of disease onset, or psychotic symptom dimensions.  Cardno et al., Biol. Psychiatry, 45:1592-1596, 1999.  A significant association between longer CAG repeats in the hKCa3/KCNN3 gene and schizophrenia in Israeli Jewish patients.  The gene was localized to chromosome 1q21.  Dror et al., Mol. Psychiatry, 4:254-260, 1999.  No association between CAG repeats and schizophrenia.  Austin et al., Mol. Psychiatry, 4:261-266, 1999.

dopamine receptor, subtype 3 (DR3) [HGL]
    A polymorphism in the first exon of the dopamine receptor, subtype 3 (DR3), has been observed, resulting in an amino acid substitution of a glycine for a serine at position 9 (Ser9Gly).  Several studies, including this one, have reported an association of the Ser9Gly polymorphism with schizophrenia.  In addition to the Ser9Gly polymorphism, several polymorphisms in the 5' promoter region were also been observed.  Although these 5' polymorphisms were not linked to schizophrenia, it appears they are linkage disequilibrium with unknown loci associated with schizophrenia.  Ishiguro et al., Mol. Psych., 5:433-438, 2000.  A tentative trend associating a polymorphic marker in close proximity to the DR3 gene was observed in Swedish patients with schizophrenia.  Jonsson et al., Am. J. Med. Genet., 88:352-357, 1999.

dopamine receptor, subtype 4 (DR4) [HGL]
    Polymorphisms in the third exon of the dopamine receptor, subtype 4 (DR4), have been identified which result in different lengths of the third cytoplasmic loop.  This part of the receptor is involved in coupling of DR4 to G-proteins.  No differences were observed between controls and schizophrenic in the 25 different polymorphisms analyzed.  This is consistent with some studies, but not others.  However, patients with catatonic schizophrenia more frequently carried 2 of the 25 polymorphisms than either controls or other schizophrenics, suggesting a possible link between this phenotype and DR4.  Since the number of patients with this type of schizophrenia was small, further studies are necessary to confirm these results.  Kaiser et al., Mol. Psych., 5:418-424, 2000.

NMDA receptor, subunit NR1 [GE]
    Transgenic mice were produced which expressed only 5% of normal levels of the NMDA receptor subunit NR1.  These showed various behavioral abnormalities, including increased motor activity, stereotypy, and deficits in social and sexual interactions, behaviors oftens observed in animal models for schizophrenia.  These abnormalities were relieved by antipsychotic drugs, such as haloperidol or clozapine, suggesting that NMDA receptors play a role in schizophrenia-like behaviors.  Mohn et al., Cell, 98:427-436, 1999.

serotonin receptor, type 6 (5-HTR6) [HGL]
    A variant allele, C267T, of the human serotonin type 6 receptor (5-HTR6) was studied in schizophrenic and normal patients.  There was a significant difference in the 5-HTR6 genotype between schizophrenic and normal controls, suggesting that the 5HTR6 gene play a role in the pathogenesis of schizophrenic disorders.  No correlation was seen between patients with, or without, aggressive behavior associated with schizophrenia.  Tsai et al., Neurosci. Lett., 271:135-137, 1999.

tissue necrotic factor-alpha (TNF-alpha) [HGL]
     Dysregulation in cytokine production (TNF-alpha, IL-1 and Il-6) has been previously observed in schizophrenics.  Human tissue necrotic factor-alpha (TNF-alpha) is a cytokine that plays a role in inflammation.  Several polymorphisms in the promoter region of the TNF-alpha gene have been identified.  One of the polymorphisms is in the TNF-alpha promoter region, at nucleotide position -308, and has been shown to directly affect TNF-alpha expression.  One common variant has a guanine at -308 and is called TNF1.  A rare variant, TNF2, having an adenine at position -308, has also been identified.  When compared to normal controls, a significant increase of the TNF2 allele was identified in a population of schizophrenic patients.  Boin et al., Mol. Psychiatry, 6:79-82, 2001.