Tadashi Umekage

Association of the oxytocin receptor (OXTR) gene polymorphisms with autism spectrum disorder (ASD) in the Japanese population.

The oxytocin receptor (OXTR) gene, which is located on chromosome 3p25.3, has been implicated as a candidate gene for susceptibility of autism spectrum disorder (ASD). Positive associations between OXTR and ASD have been reported in earlier studies. However, the results were inconsistent and demand further studies. In this study, we investigated the associations between OXTR and ASD in a Japanese population by analyzing 11 single-nucleotide polymorphisms (SNPs) using both family-based association test (FBAT) and population-based case–control test. No significant signal was detected in the FBAT test. However, significant differences were observed in allelic frequencies of four SNPs, including rs2254298 between patients and controls. The risk allele of rs2254298 was ‘A’, which was consistent with the previous study in Chinese, and not with the observations in Caucasian. The difference in the risk allele of this SNP in previous studies might be attributable to an ethnic difference in the linkage disequilibrium structure between the Asians and Caucasians. In addition, haplotype analysis exhibits a significant association between a five-SNP haplotype and ASD, including rs22542898. In conclusion, our study might support that OXTR has a significant role in conferring the risk of ASD in the Japanese population.

Genome-wide association study of panic disorder in the Japanese population.

Panic disorder (PD) is an anxiety disorder characterized by panic attacks and anticipatory anxiety. Although a number of association studies have been conducted, no gene has been identified as a susceptibility locus. In this study, we conducted a genome-wide association study of PD in 200 Japanese patients and the same number of controls, using the GeneChip Human Mapping 500 K Array Set. Genotypes were determined using the Bayesian Robust Linear Model with Mahalanobis (BRLMM) genotype calling algorithm. The genotype data were data-cleaned using criteria for SNP call rate (⩾95%), Hardy–Weinberg equilibrium (P⩾0.1%) and minor allele frequency (⩾5%). The significance level of the allele P-value was set at 1.0 × 10−6, to make false discovery rate (FDR) <0.05. As a result, seven SNPs were significantly associated with PD, which were located in or adjacent to genes including PKP1, PLEKHG1, TMEM16B, CALCOCO1, SDK2 and CLU (or APO-J). Studies with other samples are required to confirm the results.

Association between the neurofibromatosis-1 (NF1) locus and autism in the Japanese population

Autistic patients have a 100 to 190‐fold increased risk of neurofibromatosis compared to the general population. This suggests that the two diseases may share a common etiological background. Recently, a new allele (or the six‐repeat allele) of the (AAAT)n repeat polymorphism in an Alu sequence in the neurofibromatosis‐1 (NF1) gene was observed exclusively in severe autistic patients, not in controls, in Caucasians of French ancestry. This suggests a role of the NF1 gene in the development of autism. We investigated three microsatellite polymorphisms within the intron‐27b and intron‐38 of the NF1 region, including the (AAAT)n and two (CA)n repeat polymorphisms, in Japanese subjects with autism (n = 74) and controls (n = 122). The six‐repeat allele of the (AAAT)n polymorphism was not found either in patients or controls, possibly indicating an ethnic difference in the polymorphism. However, significant differences were observed in the allele distributions of the (AAAT)n and a (CA)n, which were located at intron‐27b, between patients and controls, although an association was not significant between autism and another polymorphism at intron‐38. This may suggest an involvement of the NF1 locus in susceptibility to autism, although further investigations are recommended.

Association of mitochondrial complex I subunit gene NDUFV2 at 18p11 with schizophrenia in the Japanese population.

Schizophrenia and bipolar disorder share common genetic background. Several loci such as 18p11, 13q32, and 22q11–13 were commonly linked with these diseases. Since mitochondrial dysfunction has been suggested in both of these disorders, NDUFV2 at 18p11, encoding a subunit of the complex I, NADH ubiquinone oxidoreductase, is a candidate gene for these diseases. We previously reported that single nucleotide polymorphisms (SNPs) in the upstream region of NDUFV2 were associated with bipolar disorder in Japanese. The association of haplotype consisting of two SNPs, −3542G > A and −602G > A, with bipolar disorder was also seen both in Japanese and the National Institute of Mental Health Pedigrees trios. In this study, 2 polymorphisms, −3542G > A and −602G > A, were investigated in 229 schizophrenic patients as compared with controls. Individual genotypes were not associated with schizophrenia. However, the haplotype consisting of these two SNPs were significantly associated with schizophrenia. These results suggested that inter‐individual variation of the genomic sequence of the promoter region of NDUFV2 might be a genetic risk factor common to bipolar disorder and schizophrenia.

Association of the XBP1-116C/G polymorphism with schizophrenia in the Japanese population.

Abstract  Schizophrenia and bipolar disorder share some clinical features and linkage studies have shown that several loci are common. Recently, the authors found that the −116C→G substitution in the promotor region of XBP1, a pivotal gene in endoplasmic reticulum (ER) stress response, causes the impairment of ER stress response, and that the −116C/C genotype is a protective factor; in other words the presence of the G allele increases the risk for bipolar disorder. The gene is located on 22q12.1, which is also linked with schizophrenia. The polymorphisms were investigated in 234 schizophrenic patients as compared with controls. Significant difference of genotype distribution was observed, which suggested that the −116C/C genotype is a protective factor for both of the major mental disorders.

Combined analysis of association between personality traits and three functional polymorphisms in the tyrosine hydroxylase, monoamine oxidase A, and catechol-O-methyltransferase genes

Several molecular genetic studies have been conducted with regard to the association between catecholamine-related genes and personality traits. However, the results of replication studies did not always coincide. One of the possible reasons may be that the effect exerted by the individual gene is small. In the present study, we investigated the association between personality traits and systematic combination of functional polymorphisms in three genes that regulate the metabolism of catecholamines, namely, tyrosine hydroxylase (TH), monoamine oxidase A (MAOA), and catechol-O-methyltransferase (COMT). The (TCAT)n repeat in the TH gene, the promoter variable number tandem repeat (VNTR) in the MAOA gene, and Val158Met in the COMT gene were genotyped in 256 healthy Japanese volunteers. Personality traits were evaluated using the NEO Personality Inventory-Revised (NEO PI-R). As a result, the score for Neuroticism increased, and those for Extraversion and Conscientiousness decreased according to the degree of functional polymorphic change, i.e., the lower synthesis/higher catalysis of catecholamines. A statistically significant difference was observed in the change of Extraversion (p=0.04, after Bonferroni correction). These results may provide evidence for the association between metabolic change of catecholamines and personality traits, which may be due to the additive effect of the three genes.

Meta-analysis of genome-wide association studies for panic disorder in the Japanese population

Panic disorder (PD) is a moderately heritable anxiety disorder whose pathogenesis is not well understood. Due to the lack of power in previous association studies, genes that are truly associated with PD might not be detected. In this study, we conducted a genome-wide association study (GWAS) in two independent data sets using the Affymetrix Mapping 500K Array or Genome-Wide Human SNP Array 6.0. We obtained imputed genotypes for each GWAS and performed a meta-analysis of two GWAS data sets (718 cases and 1717 controls). For follow-up, 12 single-nucleotide polymorphisms (SNPs) were tested in 329 cases and 861 controls. Gene ontology enrichment and candidate gene analyses were conducted using the GWAS or meta-analysis results. We also applied the polygenic score analysis to our two GWAS samples to test the hypothesis of polygenic components contributing to PD. Although genome-wide significant SNPs were not detected in either of the GWAS nor the meta-analysis, suggestive associations were observed in several loci such as BDKRB2 (P=1.3 × 10−5, odds ratio=1.31). Among previous candidate genes, supportive evidence for association of NPY5R with PD was obtained (gene-wise corrected P=6.4 × 10−4). Polygenic scores calculated from weakly associated SNPs (P<0.3 and 0.4) in the discovery sample were significantly associated with PD status in the target sample in both directions (sample I to sample II and vice versa) (P<0.05). Our findings suggest that large sets of common variants of small effects collectively account for risk of PD.

Six-Year Stability of Affective Temperaments as Measured by TEMPS-A

Background: A number of psychopathological and neurobiological studies on affective temperament have been conducted based on the assumption that temperament is a stable trait. However, few studies have actually assessed the long-term stability of affective temperament. The objective of this study is to evaluate the 6-year stability of affective temperaments as measured by the Temperament Evaluation of Memphis, Pisa, Paris and San Diego – Autoquestionnaire version (TEMPS-A) in a non-clinical adult population. Sampling and Methods: Study participants consisted of 178 Japanese white-collar workers (103 males and 75 females; mean age = 38.5 years, SD = 7.8) who completed the Japanese version of TEMPS-A twice over a 6-year interval, and who did not have either past or current DSM-IV affective, anxiety or psychotic disorders, as diagnosed with the Mini-International Neuropsychiatric Interview. The long-term stability of affective temperaments as measured by TEMPS-A was assessed by analyzing Pearson correlation coefficients for temperament scores over a 6-year period. Results: Temperament scores were moderately to highly correlated over the 6-year period (depressive temperament, r = 0.59; cyclothymic temperament, r = 0.68; hyperthymic temperament, r = 0.82; irritable temperament, r = 0.66; anxious temperament, r = 0.74; p < 0.01 for all values). Pearson coefficients were in the range of 0.61–0.83 for males and 0.51–0.79 for females, while they were 0.56–0.85 for younger and 0.63–0.77 for older participants. All correlations were significant at p < 0.01, irrespective of temperament type, gender and age. Conclusions: Affective temperaments as measured by TEMPS-A exhibited good long-term stability and were robust, irrespective of temperament type, gender and age. Affective temperaments as measured by TEMPS-A may be considered to be stable traits, providing a sound basis for psychopathological and neurobiological studies. Limitations of this study include the fact that our sample was not drawn from the general community, it was entirely composed of Japanese participants and the size was not large.

Association between dopamine D4 receptor (DRD4) exon III polymorphism and Neuroticism in the Japanese population

The association between the dopamine D4 receptor (DRD4) exon III polymorphism and personality trait of novelty seeking (NS) has been studied intensively. In the Japanese population, the results of the previous studies did not always coincide. In the present study, we investigated the association between the polymorphism and personality traits evaluated by using the Revised NEO Personality Inventory (NEO PI-R) and State-Trait Anxiety Inventory (STAI) in 196 Japanese subjects. A meta-analysis of the present and previous Japanese studies was also conducted regarding NS. As a result, significant association was observed between the polymorphism and personality traits evaluated by using NEO PI-R as a whole (p=0.022, MANCOVA). Subsequent analyses showed a significant association between short alleles (2-4 repeats) and higher scores for Neuroticism or its subscales, Anxiety, Depression, and Vulnerability (p=0.015, 0.039, 0.021, and 0.008, respectively, uncorrected). No other significant difference in the scores for NEO PI-R was observed in the subsequent analyses. Significant association was also observed between the polymorphism and scores for STAI as a whole (p=0.004, MANCOVA). Subsequent analyses did not show significant association, although a weak trend for the relation between the genotype consisting of short alleles and Trait Anxiety was observed (p=0.10, uncorrected). The meta-analysis showed no significant association between the polymorphism and NS. Thus, the present study suggested the association between the short allele of the DRD4 exon III polymorphism and personality trait of Neuroticism in Japanese subjects.

Molecular genetic studies of schizophrenia: challenges and insights.

Schizophrenia (SCZ) is a mental disease that affects approximately 1% of the population with life-long devastating consequences. Based on evidence for a major contribution of genetic factors, a decade of extensive efforts has been dedicated to the search of DNA sequence variations that increase the risk to SCZ. Search for genes in rare multiplex SCZ families with a large number of affected individuals and quasi-Mendelian mode of inheritance using genetic linkage methodology has been one of the favorite strategies in psychiatric genetics. Although several genomic regions were suggested for linkage to SCZ, not a single gene causing or predisposing to SCZ has been identified thus far. Furthermore, it is not clear whether the genes of familial SCZ are also involved in sporadic cases that represent the overwhelming majority of SCZ patients. For sporadic cases, genetic association studies comparing the distribution of allelic frequencies of candidate genes in SCZ patients and controls have been performed but the outcome of such studies has also been quite modest. Several factors such as possible involvement of numerous interactive genes of minor effect, yet unknown environmental effects and diagnostic ambiguities of the disease have made genetic studies in SCZ quite unproductive. In terms of future studies, a genome-wide association search is a promising approach; however, this approach requires genotyping of thousands of genetic markers in large samples. In addition, a detailed analysis of the genes, expression of which changes under the influence of environmental factors, can indicate good candidates for genetic association studies. In this connection, investigations of the epigenetic regulation of genes and not only the DNA sequence variation, may be necessary for complete understanding of the etiopathogenic mechanisms of SCZ.