Alcohol and aldehyde dehydrogenase polymorphisms and risk for suicide: a preliminary observation in the Japanese male population.

Epidemiological studies have shown that excessive alcohol consumption is a potent risk factor to develop suicidal behavior. Genetic factors for suicidal behavior have been observed in family, twin, and adoption studies. Because alcohol dehydrogenase (ADH1B) His47Arg and mitochondrial aldehyde dehydrogenase (ALDH2) Glu487Lys single nucleotide polymorphisms (SNPs), which affect alcohol metabolism, have been reported to exert significant impacts on alcohol consumption and on the risk for alcoholism in East Asia populations, we explored associations of the two functional SNPs with suicide using a case-control study of 283 completed suicides and 319 control subjects in the Japanese population. We found that the inactive ALDH2 allele (487Lys) was significantly less frequent in the completed suicides (19.3%) than in the controls (29.3%), especially in males, whereas this was not the case in females. The males bearing alcoholism-susceptible homozygotes at both loci (inactive ADH1B Arg/Arg and active ALDH2 Glu/Glu genotypes) have a 10 times greater risk for suicide compared with the males bearing alcoholism-protective homozygotes at both loci. Our data show the genetic impact of the two polymorphisms on suicidal behavior in the Japanese population, especially in males. Because we did not verify the daily alcohol consumption, the association of these SNPs with suicide might be due to alcoholism itself. Further studies using case-control subjects, which verifies the details of current and past alcohol consumption and diagnosis for alcoholism, are required to confirm these findings.

A functional polymorphism of the micro-opioid receptor gene is associated with completed suicides.

A recent linkage study suggested that a putative locus for suicidal behavior independent of psychiatric disease phenotypes lies at 5' upstream of the micro-opioid receptor (OPRM1) gene. We explored an association between suicide and genetic variations of the OPRM1 using a case-control study of 183 completed suicides and 374 control subjects. We genotyped four single nucleotide polymorphisms (SNPs) including a common A118G SNP. The genotypic and allelic distributions of the A118G SNP were significantly different between the completed suicide and control groups (P = 0.014 and 0.039, respectively). A dominant model analysis of the A118G SNP showed an enhanced association with suicide (P = 0.0041, Odds ratio 0.575) and this significant association was observed with a logistic regression analysis that takes sex and age factors into account (P = 0.021). Our results raise the possibility that the A118G SNP of the OPRM1 gene is associated with suicide.

Association between a functional polymorphism in the renin-angiotensin system and completed suicide.

Suicide has been suggested to involve disturbances in the stress response system and to be related to genetics. The renin-angiotensin system (RAS) has been shown to affect the stress response, and several functional polymorphisms in RAS-related genes have been predicted to alter protein function. We hypothesized that the dysregulation of RAS was involved in suicide, and examined the association between completed suicides and four functional polymorphisms of RAS-related genes: the angiotensinogen M235T, angiotensin-converting enzyme (ACE) insertion(I)/deletion(D), angiotensin type-1 receptor A1166C, and G-protein-beta3 C825T gene polymorphisms. The I allele of the ACE I/D polymorphism was found to be more frequent in completed suicides than in controls (P = 0.014). The I allele was also found to be more frequent in male completed suicides (P = 0.022) than in male controls, while this was not the case in females. These results suggest that the alteration of RAS function caused by the genetic polymorphism is involved in the susceptibility to suicide in males.

Tryptophan hydroxylase immunoreactivity is altered by the genetic variation in postmortem brain samples of both suicide victims and controls.

Several lines of evidence suggest that a partly genetically controlled serotonergic dysfunction is involved in the biological pathogenesis of suicide. In this study, we measured tryptophan hydroxylase (TPH) immunoreactivity as a pre-synaptic marker, and serotonin receptor 2A (5HT2A receptor) density as a post-synaptic marker in the serotonergic system in 10 postmortem brains of suicide victims. We also examined whether TPH gene polymorphisms (A218C and A-6526G polymorphisms) could affect TPH immunoreactivity and 5HT2A receptor gene polymorphism (A-1438G polymorphism) could affect 5HT2A receptor density in 28 postmortem brain samples. No significant differences were found in TPH immunoreactivity or 5HT2A receptor density between suicide victims and controls. The AA genotype of the A218C polymorphism of the TPH gene showed higher TPH immunoreactivity along with lower 5HT2A receptor density than did any other genotypes in the postmortem brains of both suicide victims and controls. Our findings suggest that the A218C polymorphism of the TPH gene can be expected to provide new insights not only for neurobiological studies of suicide, but also for research into the behavioral characteristics that may be associated with serotonergic dysfunction.

Association between 5HT2A receptor gene promoter region polymorphism and eating disorders in Japanese patients.

BACKGROUND: Evidence from family and twin studies suggests a genetic contribution to the etiology of eating disorders (EDs). Recently, researchers have reported genetic associations between the MspI polymorphism (-1438A/G) of the promoter region of the 5HT2A receptor gene and EDs; however, reports of evidence against these findings make the association controversial. METHODS: The authors examined the prevalence of the -1438A/G polymorphism of the 5HT2A receptor gene among 182 Japanese patients with EDs and 374 normal control subjects. Interactions of the association of this polymorphism with subtypes of anorexia nervosa (AN), bulimia nervosa (BN), and various clinical characteristics were also assessed. RESULTS: In contrast to previous studies reporting elevated A allele frequencies in patients with AN, the G allele had a significantly higher frequency in patients with BN but not in patients with AN, than in control subjects. Examination of the interactions revealed that the presence of the binge eating and/or purging behavior and comorbid borderline personality disorder (BPD) tended to be associated with increased frequency of the G allele. CONCLUSIONS: Though preliminary, these results can be interpreted as suggesting that the G allele of the 5HT2A receptor gene -1438A/G polymorphism may be associated with pathological features that EDs and BPD have in common, especially disinhibition in eating behavior and personality trait.

Serotonin 2A receptor gene polymorphism is not associated with completed suicide.

Several lines of evidence indicate that a serotonergic dysfunction is involved in the biological susceptibility to suicide. Recently, the A-1438G polymorphism of the serotonin 2A (5-HT2A) receptor gene has been suggested to be associated with suicide, but the results are inconsistent. We examined whether the A-1438G polymorphism of the 5-HT2A receptor gene was associated with suicide itself using 151 Japanese completed suicides. No significant difference in genotype distribution or allele frequencies of the polymorphism was found between the completed suicides and the comparison group. We conclude that the A-1438G polymorphism of the 5-HT2A receptor gene is not likely to have a major effect on the biological susceptibility of suicide.

Abnormal neurochemical asymmetry in the temporal lobe of schizophrenia.

Neuroanatomical asymmetries are known to be present in the human brain, and loss of reversal of these asymmetries, particularly through changes in the left temporal lobe, have been found in the brains of patients with schizophrenia. In addition to disturbed neuroanatomical asymmetries, disturbed neurochemical asymmetries have also been reported in the brains of patients with schizophrenia. However, in the temporal lobe, the laterality of most of these neurochemical changes has not been specifically evaluated. Few neurochemical studies have addressed left-right differences in the superior temporal gyrus (STG). A deteriorated serotonin2A receptor-G protein qalpha (Gqalpha)-phosphoinositide-specific phospholipase C beta1(PLC beta1) cascade has been found in the left, but not right, STG of patients with schizophrenia. Not only neuroanatomical but also neurochemical evidence supports the loss or reversal of normal asymmetry of the temporal lobe in schizophrenia, which might be due to a disruption of the neurodevelopmental processes involved in hemispheric lateralization.

No evidence of an association between 5HT1B receptor gene polymorphism and suicide victims in a Japanese population.

Serotonergic systems have been reported to mediate the control of aggression and/or impulsivity in humans and to be involved in suicidal behavior. Neurochemical studies showing serotonergic dysfunction in suicide appear to support the functional alteration of serotonergic systems due to gene polymorphisms. Knock-out mice of the 5HT1B receptor gene have been reported to result in increased aggression. We hypothesized that the 5HT1B receptor-mediated serotonergic dysfunction was implicated in suicide through disinhibition of aggression and/or impulsivity. To explore this hypothesis, we examined the association between suicide victims who completed suicide and the 5HT1B receptor gene G861C polymorphism. No significant differences in genotype distribution and allele frequencies were found between suicide victims and controls. Though there is the possibility of failing to detect small effects, these results show no evidence of an association between the 5HT1B receptor gene G861C polymorphism and suicide victims in a Japanese population and indicate that it is unlikely that the 5HT1B receptor is implicated in the susceptibility to suicide.

Tryptophan hydroxylase gene polymorphisms are not associated with suicide.

Several lines of evidence suggest a serotonergic dysfunction involved in the biological susceptibility of suicide. Abnormalities of serotonergic markers such as 5-hydroxyindoleacetic acid and prolactin response to fenfluramine have been demonstrated in suicide subjects. Tryptophan hydroxylase (TPH), the rate-limiting enzyme in serotonin biosynthesis, is one of the most important regulating factors in the serotonergic system. Recently, polymorphisms of the TPH gene have been identified and some of these polymorphisms have been suggested to be associated with suicide, but the results are still inconsistent. We examined whether the -6526A/G polymorphism in the promoter region and the 218A/C polymorphism in intron 7 of the TPH gene were associated with suicide using 132 Japanese suicide victims. No significant difference in genotype distribution and allele frequencies of these polymorphisms was found between the suicide victims and the controls. We concluded neither the -6526A/G polymorphism nor the 218A/C polymorphism of the TPH gene is likely to have a major effect on the susceptibility of suicide. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:861-863, 2000.

Abnormal expression of brain-derived neurotrophic factor and its receptor in the corticolimbic system of schizophrenic patients.

Previous neuropathological studies have revealed that the corticolimbic system of schizophrenic patients expresses abnormal levels of various synaptic molecules, which are known to be influenced by the neuronal differentiation factors, neurotrophins. Therefore, we determined levels of neurotrophins and their receptors in the postmortem brains of schizophrenic patients and control subjects in relation to molecular impairments in schizophrenia. Among the neurotrophins examined, levels of brain-derived neurotrophic factor (BDNF) were elevated specifically in the anterior cingulate cortex and hippocampus of schizophrenic patients, but levels of nerve growth factors and neurotrophin-3 showed no change in any of the regions examined. In parallel, the expressions of TrkB receptor and calbindin-D, which are both influenced by BDNF, were reduced significantly in the hippocampus or the prefrontal cortex. However, neuroleptic treatment did not appear to mimic the neurotrophic change. Neither withdrawal of drug treatment in patients nor chronic administration of haloperidol to rats altered levels of BDNF. These findings suggest that neurotrophic abnormality is associated with the corticolimbic structures of schizophrenic patients and might provide the molecular substrate for pathological manifestations of the illness.

Novel polymorphism in the gene region encoding the carboxyl-terminal intracellular domain of the NMDA receptor 2B subunit: analysis of association with schizophrenia.

OBJECTIVE: N-methyl-D-aspartate (NMDA) receptor antagonists are known to produce a syndrome resembling schizophrenia, probably due to their blockade of NMDA receptors. The NMDA receptor 2B (NR2B) subunit has been identified as one of the major proteins in the postsynaptic density at glutamatergic synapses, suggesting that the carboxyl-terminal domain of the NR2B subunit may play a significant role in intracellular signal transduction. METHOD: The authors screened for genetic variations in the region of the NR2B subunit gene encoding the carboxyl-terminal intracellular domain in patients with schizophrenia and studied the association between schizophrenia and a novel polymorphism of the NR2B subunit gene. RESULTS: One silent mutation (2664C/T) was identified. No significant differences in the frequencies of 2664C/T genotypes and alleles were found between patients with schizophrenia and healthy comparison subjects. CONCLUSIONS: The findings provided no evidence of an association between schizophrenia and the 2664C/T polymorphism of the NR2B subunit gene.

Association study of a polymorphism of nonerythroid alpha-spectrin gene with schizophrenia.

The specificity of cytoarchitectural abnormalities in limbic structures of patients with schizophrenia and their contributions towards the etiology of schizophrenia remain unknown. We have recently reported an increased breakdown of nonerythroid alpha-spectrin (fodrin), a major component of neuronal cytoskeletal proteins, in schizophrenic left superior temporal cortices [Kitamura et al., 1998: Biol Psychiatry 43:254-262], suggesting that polymorphisms of the alpha-spectrin gene might contribute to the vulnerability to schizophrenia. We screened for genetic variations associated with schizophrenia through the C-terminus sequences of the human nonerythroid alpha-spectrin gene (SPTAN1) spanning two EF-hands and also tested a possible contribution of the polymorphism to the development of schizophrenia by an association study. We found a polymorphic region of an intron located in the second EF-hand of SPTAN1 gene. There was no significant difference between patients with schizophrenia and controls in allele frequencies or genotype distribution. There is evidence that the Psh BI SPTAN1 gene polymorphism does not play a major role in the genetic component of schizophrenia.

Opposite changes in phosphoinositide-specific phospholipase C immunoreactivity in the left prefrontal and superior temporal cortex of patients with chronic schizophrenia.

BACKGROUND: Abnormalities in types of neurotransmitter signaling that are coupled with phosphoinositide-specific phospholipase C (PLC) have previously been reported in brains from patients with schizophrenia. PLC, a main component of this pathway, may be affected in schizophrenia. METHODS: We immunoquantified PLC beta 1, gamma 1 and delta 1 in the left prefrontal cortex and superior temporal cortex, nucleus accumbens and amygdala, and in the right superior temporal cortex of postmortem brains obtained from a total of 19 patients with schizophrenia and a total of 27 controls. RESULTS: PLC beta 1 immunoreactivities were increased in the particulate fraction from the prefrontal cortex (by 64%), although they were decreased in the particulate fraction from the left superior temporal cortex (by 28%), as compared with the values in controls. There was no difference in PLC beta 1 immunoreactivities in the nucleus accumbens, the amygdala or the right superior temporal cortex between schizophrenic patients and controls. PLC gamma 1 and delta 1 immunoreactivities did not differ between the two groups in any of the regions studied. CONCLUSIONS: Changes in PLC beta 1 immunoreactivities in the prefrontal and superior temporal cortex of patients with schizophrenia may reflect abnormalities in neurotransmissions via receptors that are coupled with the Gq alpha-PLC beta 1 cascade.

Striatal enlargement in rats chronically treated with neuroleptic.

BACKGROUND: Striatal enlargement with chronic neuroleptic treatment in schizophrenic patients has been reported by several investigators. Longitudinal magnetic resonance imaging studies of patients suggest that changes in striatal volume may be caused by treatment with antipsychotic medication. METHODS: We have examined the effects of chronic neuroleptic treatment on postmortem striatal volume in the laboratory rat and have examined the relationship between striatal volume and vacuous chewing movements (VCMs). Autoradiographs of 50 rats treated with haloperidol (1.5 mg/kg/day) or drug free for varying durations of time (1-12 months) were utilized in this analysis. RESULTS: Chronic treatment with neuroleptics (1 month or greater) was associated with larger striatal volumes. The increase in striatal volume was present at 1 month of treatment and was sustained to 12 months of treatment. Rats that developed the high-VCM syndrome had larger striatal volumes than both drug-free and low-VCM rats, while low-VCM rats had larger striatal volumes than drug-free rats. CONCLUSIONS: These data suggest that chronic neuroleptic treatment is the cause of striatal enlargement in the laboratory rat, and that this enlargement is most prominent in rats that have the high-VCM syndrome.

Asymmetrical changes in the fodrin alpha subunit in the superior temporal cortices in schizophrenia.

BACKGROUND: We examined possible abnormalities in neural structural proteins that may underlie morphometric changes reported in the left superior temporal cortices (Brodmann's area 22) of schizophrenics. METHODS: Particulate proteins of the superior temporal cortices taken at autopsy from 11 schizophrenic and 9 control brains were fractionated by gel electrophoresis. Target proteins, identified by reading their amino acid sequences, were immunoquantified using the specific antibody. RESULTS: Amino acid sequences of the 150-kDa proteins on sodium dodecyl sulfate/polyacrylamide gel electrophoresis, which were significantly increased on the left side of schizophrenic superior temporal cortices, revealed that they were proteolytic fragments of the alpha subunit of fodrin, a major cytoskeletal protein underlying the plasma membrane. Immunoquantification using the specific antibodies against alpha and beta subunits of fodrin indicated that there exist concomitant decreases in the full-length 240-kDa form and increases in the 150-kDa form of alpha-fodrin with no changes of the 235-kDa form of beta-fodrin in the left superior temporal cortices of the schizophrenic brains. CONCLUSIONS: The findings may be a possible molecular basis for linking morphometric changes to neurochemical pathophysiology in schizophrenia.

Isotype-specific G protein abnormalities in the left superior temporal cortex and limbic structures of patients with chronic schizophrenia.

BACKGROUND: The potential role of signal transducing guanine nucleotide-binding regulatory protein (G protein) in schizophrenia is largely unknown. METHODS: We immunoquantified isotypes of G protein using specific antisera against alpha and beta subunits of G protein in the superior temporal, prefrontal, and entorhinal cortices as well as the nucleus accumbens and amygdala of postmortem brains from 19 schizophrenic and 28 control subjects. RESULTS: In the left hemisphere of schizophrenics, the amount of Gi alpha, Go alpha, and Gq alpha but not that of Gs alpha or G beta decreased in the superior temporal cortex by 27%, 27%, and 16%, respectively, as compared with the values in ipsilateral controls; the amount of any G protein isotype in the prefrontal and entorhinal cortices was not changed. In the nucleus accumbens and amygdala, the paranoid type schizophrenics showed a smaller amount of Gi alpha and Go alpha than the disorganized type schizophrenics. In the right superior temporal cortex, the isotype amount did not differ between the schizophrenic and control groups. CONCLUSIONS: The decreased Gq alpha immunoreactivity in the schizophrenic left superior temporal cortex may reflect the down-regulation of Gq alpha, resulting from chronic stimulation of Gq alpha-coupled receptors, while the decreased Gi alpha and Go alpha in the nucleus accumbens and amygdala of paranoid type schizophrenics may be related to the dopaminergic hyperactivity via dopamine D2 receptors.

Increased striatal glutamate transporter by repeated intermittent administration of methamphetamine.

We have examined the immunoreactivities of a glutamate (Glu) transporter, GLT-1, in rat brains treated with a single or repeated intermittent administration of methamphetamine (MAP). In the stratum of behaviorally sensitized rate induced by repeated intermittent MAP treatment, GLT-1 immunoreactivities were increased by 51%. There was no difference in the GLT-1 immunoreactivities in all regions examined between rate treated with a single administration of MAP and the control rats. These results suggest that hyperglutamatergic activity in the striatum is involved in the induction of behavioral sensitization caused by MAP.

Delayed changes in neural visinin-like calcium-binding protein gene expression caused by acute phencyclidine administration.

Phencyclidine (PCP) induces a psychotomimetic state that closely resembles schizophrenia, and PCP-treated animals can serve as a model for schizophrenia. The effects of PCP on the gene expression of NVP-1, a novel Ca(2+)-binding protein, were studied in rats. After 24 hours, the NVP-1 mRNA level in the nucleus accumbens showed a significant decrease of 42%. This result suggests that alterations in Ca(2+)-binding protein may be involved in the pathology of PCP-induced psychosis and, presumably, schizophrenia.