Kenshiro Ohara

Low activity allele of catechol-o-methyltransferase gene and Japanese unipolar depression.

SEVERAL studies have shown that depressed patients have significantly lower catechol-o-methyltransferase (COMT) activity than healthy controls. Two COMT genes coding for low activity, COMTL, and high activity, COMTH have been identified. We undertook an association study on 75 depressive disorder patients, 40 bipolar disorder patients and 135 healthy controls. All the subjects were Japanese. Patients with depressive disorders exhibited a significantly higher rate of genotypes with the COMTL allele than healthy controls (p = 0.012), which was not the case in patients with bipolar disorders. The presence of the COMTL allele was significantly associated with depressive disorders (odds ratio 2.19, 95% CI 1.19–4.03). Our results suggest the COMTL allele contributed to the etiologies of depressive disorders.

Daily rhythm of serum melatonin in patients with dementia of the degenerate type

The daily rhythm in serum melatonin levels was measured in patients with dementia of the degenerate type (Alzheimers disease, Picks disease and senile dementia of the Alzheimer type) by radioimmunoassay. Thirteen patients (age: 69.0 +/- 8.0 years, mean +/- S.D.) were studied. All patients were hospitalized at the time of the study and had a history of sleep-wake disturbances, nocturnal wandering and/or delirium. We also studied 13 age-matched healthy control subjects (control group 1), ten young adults (control group 2), and nine hospitalized patients without dementia (control group 3). Two subjects in the control groups showed no measurable changes in melatonin level throughout the day, while the other 30 control subjects exhibited a clear daily rhythm with the peak concentration occurring during the night. On the other hand, four out of the 13 patients with dementia did not show any melatonin rhythm. Two of the demented patients who did not exhibit melatonin rhythm displayed clinical symptoms of rhythm disorders. One out of the nine patients with melatonin rhythm presented with clinical symptoms, such as delirium and sleep-wake disturbance. Our results suggest that the probability of absent melatonin rhythm is higher in demented patients compared with subjects without dementia. However, a lack of melatonin rhythm is not always associated with symptomatic rhythm disorders. Since the melatonin rhythm reflects that of the suprachiasmatic nucleus, it follows that the SCN function of the patients having a history of rhythm disorders was not always severely damaged.

No association between anxiety disorders and catechol-O-methyltransferase polymorphism

Several studies have shown that the morbidity risk for anxiety disorders is increased among the relatives of patients with obsessive-compulsive disorder (OCD). Recently, it was reported that a polymorphism of the catechol-O-methyltransferase (COMT) gene is significantly associated with OCD. The purpose of this study was to determine the association, if any, between the COMT polymorphism and anxiety disorders. We undertook an association study of the COMT polymorphism in 108 patients who met DSM-IV criteria for anxiety disorders and 135 healthy controls. All subjects were unrelated Japanese. The subdiagnostic groups did not differ significantly from the control group in either the genotypic or allelic frequencies. There were no statistically significant differences between the genotype and males, females, or a family history. The mean age of onset did not significantly differ among the genotypes. Our results suggest this functional COMT polymorphism does not make an important contribution to anxiety disorders in the Japanese population.

Serotonin2A receptor gene polymorphism in mood disorders

Genes that regulate the serotonin (5-HT) system including 5-HT receptors may be involved in mood disorders. We studied 5-HT2A receptor exons and the adjacent intron regions in 102 patients with mood disorders (71 depressive disorders and 31 bipolar disorders). In 34 mood disorder cases, the gene encoding the 5-HT1A receptor had been sequenced, but no disease-specific polymorphism was found. The substitution of C for T at position 102 in exon 1, which had been reported by Warren et al., was confirmed. The corresponding amino acid, serine, did not change. The allele frequency of C [corrected] at position 102 was significantly higher in patients with depressive disorders than in those with bipolar disorders and healthy control subjects. Furthermore, the mean age of onset in the patients heterozyous for the T and C alleles was lower than that in those homozygous for the C allele. No other polymorphism in the gene was found.

Genomewide High-Density SNP Linkage Analysis of 236 Japanese Families Supports the Existence of Schizophrenia Susceptibility Loci on Chromosomes 1p, 14q, and 20p

The Japanese Schizophrenia Sib-Pair Linkage Group (JSSLG) is a multisite collaborative study group that was organized to create a national resource for affected sib pair (ASP) studies of schizophrenia in Japan. We used a high-density single-nucleotide-polymorphism (SNP) genotyping assay, the Illumina BeadArray linkage mapping panel (version 4) comprising 5,861 SNPs, to perform a genomewide linkage analysis of JSSLG samples comprising 236 Japanese families with 268 nonindependent ASPs with schizophrenia. All subjects were Japanese. Among these families, 122 families comprised the same subjects analyzed with short tandem repeat markers. All the probands and their siblings, with the exception of seven siblings with schizoaffective disorder, had schizophrenia. After excluding SNPs with high linkage disequilibrium, we found significant evidence of linkage of schizophrenia to chromosome 1p21.2-1p13.2 (LOD=3.39) and suggestive evidence of linkage to 14q11.2 (LOD=2.87), 14q11.2-q13.2 (LOD=2.33), and 20p12.1-p11.2 (LOD=2.33). Although linkage to these regions has received little attention, these regions are included in or partially overlap the 10 regions reported by Lewis et al. that passed the two aggregate criteria of a meta-analysis. Results of the present study--which, to our knowledge, is the first genomewide analysis of schizophrenia in ASPs of a single Asian ethnicity that is comparable to the analyses done of ASPs of European descent--indicate the existence of schizophrenia susceptibility loci that are common to different ethnic groups but that likely have different ethnicity-specific effects.

Functional polymorphism in the serotonin transporter promoter at the SLC6A4 locus and mood disorders

BACKGROUND Heils et al found a functional polymorphism in the transcriptional control region upstream of the serotonin transporter gene at the SLC6A4 locus. The transcriptional promoter activity of the short (s) form was less than twice that of the long (l) form of the serotonin transporter promoter gene. In addition, they found individuals with the s form with associated neurotic characteristics (e.g., anxiety, anger, hostility, and depression). The purpose of this study was to determine whether or not there is an association between this functional polymorphism and mood disorders. METHODS The l/s polymorphism was studied in 80 patients with mood disorders and 92 control subjects. RESULTS There was statistically no difference between mood disorders and healthy controls in either the genotype or the allele frequency. There was statistically no difference between the genotype and subdiagnosis, family history, single/recurrent episodes of depressive disorders, suicide attempts, or the mean age of onset. CONCLUSIONS Our results suggest there is no association between the l/s polymorphism of the serotonin transporter gene and mood disorders.

A variable-number-tandem-repeat of the serotonin transporter gene and anxiety disorders

1. A polymorphism of the variable-number-tandem-repeat (VNTR) in the second intron of the serotonin transporter (ST) gene, which has been reported to be associated with major depression, was studied in anxiety disorders. 2. The VNTR of the human ST gene was compared between 103 patients with anxiety and 106 controls. 3. The frequency of the allele containing 12 copies of the VNTR element (STin2.12) was significantly higher in the combined patient group (p = 0.027), and among patients with OCD (p = 0.0326), and GAD (p = 0.0123), in comparison with in controls. 4. The presence of the STin2.12 allele was significantly associated with the risk of combined anxiety disorders (odds ratio = 2.06, 95% CI 1.09-3.90), OCD (10.2, 1.34-77.4), and GAD (3.61, 1.23-10.6).

Proton magnetic resonance spectroscopy of the lenticular nuclei in bipolar I affective disorder

Proton magnetic resonance spectroscopy (1H-NMS) was used to examine the ratio of choline-containing compound (Cho) to creatine (Cr) in the basal ganglia. Subjects comprised 10 bipolar I affective disorder patients and 10 healthy control subjects. No significant difference was found in the Cho/Cr, N-acetyl-aspartate (NAA)/Cr, or NAA/Cho ratios between bipolar patients and control subjects. Within the bipolar group, negative correlations emerged between the NAA/Cr ratio in the right lenticular nuclei and both age at onset and age at the time of study. The results suggest that a late onset of illness and older age are associated with neuronal cell loss in the right lenticular nuclei in bipolar patients.

Schizophrenia and the serotonin-2A receptor promoter polymorphism

Serotonin-2A (5-HT2A) receptors have received much investigative attention in schizophrenia because (1) several studies have shown a decrease in the number of 5-HT2A receptors in the prefrontal cortex of postmortem brains of schizophrenic patients; (2) atypical antipsychotic drugs are antagonists for 5-HT2A receptors; and (3) a positive association between a T to C polymorphism at position 102 of the 5-HT2A receptor gene and schizophrenia has been reported. A G to A polymorphism at position -1438 of the 5-HT2A receptor gene was studied in 119 schizophrenic patients and 106 healthy control subjects, all of whom were Japanese. The genotype and allele frequencies did not differ between the patients and control subjects. Furthermore, the genotype frequency did not differ according to diagnostic subtype, family history, age at onset of illness, or daily dosage of antipsychotic medication. Our results suggest that the polymorphism does not contribute to the etiology or clinical characteristics of schizophrenia. However, the gene is greater than 20 kbp in length, and thus it is possible that other areas that affect expression of the gene may vary. We found that the -1438G/A variant was in linkage disequilibrium with the T102C polymorphism.

Polymorphisms of dopamine D2-like (D2, D3, and D4) receptors in schizophrenia

The result of most association studies and linkage analyses have suggested a negative association between schizophrenia and D2-like (D2, D3, and D4) receptor polymorphisms. Although the polymorphisms of the D2-like receptor in themselves may not account for the etiology of schizophrenia, they can contribute to the severity of the symptoms. Thus, we studied the associations between the polymorphisms and their combinations, and the vulnerability of schizophrenics. Fragments of the D2-like receptor genes were amplified by means of the polymerase chain reaction, and the polymorphisms were identified by the restriction fragment length polymorphism and single-stranded conformation polymorphism methods. There were no statistically significant differences in the polymorphisms and their combinations between schizophrenics and controls. Schizophrenics with D4E1(A1/A2), which contains 2 and 1 tandem repeats of a 12-base-pair sequence in exon 1, had a lower total positive symptom score before medication than schizophrenics with D4E1(A1/A1). There was no association between the polymorphisms and negative symptoms.