Takafumi Shimada

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.

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.

Replication of a genome-wide association study of panic disorder in a Japanese population

Panic disorder (PD) is an anxiety disorder characterized by recurrent and unexpected panic attacks, subsequent worry and phobic avoidance. Although a number of association and linkage studies have been conducted, no gene has been identified as a susceptibility locus. We previously conducted a genome-wide association analysis of PD in 200 Japanese patients and the same number of controls, using a 500 K single nucleotide polymorphisms (SNPs) chip. In this study, we report a replication analysis of PD using the DigTag2 assay. The second stage sample consisted of 558 Japanese patients and 566 controls. Thirty-two markers were tested in a replication sample. As a result, no significant association was found after correction for multiple testing. However, the difference was observed at the nominal allele P-value <0.05 for two SNPs (rs6733840 and rs132617). We also conducted haplotype analyses of SNPs in the APOL3 and CLU genes. Our results failed to show any significant association with PD in these genes. Further studies on these variants with a larger sample size may be worth testing to confirm the results.

A genome-wide CNV association study on panic disorder in a Japanese population

Family and twin studies have indicated that genetic factors have an important role in panic disorder (PD), whereas its pathogenesis has remained elusive. We conducted a genome-wide copy number variation (CNV) association study to elucidate the involvement of structural variants in the etiology of PD. The participants were 2055 genetically unrelated Japanese people (535 PD cases and 1520 controls). CNVs were detected using Genome-Wide Human SNP array 6.0, determined by Birdsuite and confirmed by PennCNV. They were classified as rare CNVs (found in <1% of the total sample) or common CNVs (found in ⩾5%). PLINK was used to perform global burden analysis for rare CNVs and association analysis for common CNVs. The sample yielded 2039 rare CNVs and 79 common CNVs. Significant increases in the rare CNV burden in PD cases were not found. Common duplications in 16p11.2 showed Bonferroni-corrected P-values <0.05. Individuals with PD did not exhibit an increased genome-wide rare CNV burden. Common duplications were associated with PD and found in the pericentromeric region of 16p11.2, which had been reported to be rich in low copy repeats and to harbor developmental disorders, neuropsychiatric disorders and dysmorphic features.

Genome-wide Association Study of Autism Spectrum Disorder in the East Asian Populations.

Autism spectrum disorder is a heterogeneous neurodevelopmental disorder with strong genetic basis. To identify common genetic variations conferring the risk of ASD, we performed a two‐stage genome‐wide association study using ASD family and healthy control samples obtained from East Asian populations. A total of 166 ASD families (n = 500) and 642 healthy controls from the Japanese population were used as the discovery cohort. Approximately 900,000 single nucleotide polymorphisms (SNPs) were genotyped using Affymetrix Genome‐Wide Human SNP array 6.0 chips. In the replication stage, 205 Japanese ASD cases and 184 healthy controls, as well as 418 Chinese Han trios (n = 1,254), were genotyped by TaqMan platform. Case–control analysis, family based association test, and transmission/disequilibrium test (TDT) were then conducted to test the association. In the discovery stage, significant associations were suggested for 14 loci, including 5 known ASD candidate genes: GPC6, JARID2, YTHDC2, CNTN4, and CSMD1. In addition, significant associations were identified for several novel genes with intriguing functions, such as JPH3, PTPRD, CUX1, and RIT2. After a meta‐analysis combining the Japanese replication samples, the strongest signal was found at rs16976358 (P = 6.04 × 10−7), which is located near the RIT2 gene. In summary, our results provide independent support to known ASD candidate genes and highlight a number of novel genes warranted to be further investigated in a larger sample set in an effort to improve our understanding of the genetic basis of ASD. Autism Res 2016, 9: 340–349.

Mortality of neuroleptic malignant syndrome induced by typical and atypical antipsychotic drugs: A propensity-matched analysis from the Japanese Diagnosis Procedure Combination database

OBJECTIVE Neuroleptic malignant syndrome induced by atypical antipsychotics presents atypical clinical manifestations with fewer symptoms compared with neuroleptic malignant syndrome induced by typical antipsychotics. However, any differences in prognosis between these 2 types of drug-induced neuroleptic malignant syndrome remain unknown. We examined neuroleptic malignant syndrome-related mortality in patients treated with typical or atypical antipsychotics by using a national administrative claims database. METHOD Data of patients with a diagnosis of neuroleptic malignant syndrome between July and December in each of the 5 years from 2004 to 2008 were extracted from the Japanese Diagnosis Procedure Combination database. Data included patient background, use of antipsychotics, and in-hospital mortality. Propensity score matching was performed to formulate a balanced 1:1 matched study and to compare in-hospital mortality between neuroleptic malignant syndrome patients taking typical antipsychotics and those taking atypical antipsychotics. RESULTS We identified 423 neuroleptic malignant syndrome patients treated with typical antipsychotics and 215 neuroleptic malignant syndrome patients treated with atypical antipsychotics. Matching based on propensity scores produced 210 patients in each drug group. In-hospital mortality was substantially lower in the atypical antipsychotic group compared with the typical antipsychotic group, but the difference was not significant (3.3% vs 7.6%; OR = 0.44; 95% CI, 0.17-1.11; P = .084). CONCLUSIONS The results show that neuroleptic malignant syndrome remains a life threatening disease among patients receiving antipsychotics. A tendency for lower mortality in the atypical antipsychotic group may reflect differences in the pathophysiology. However, to clarify whether there is a difference in neuroleptic malignant syndrome-related mortality with the 2 types of antipsychotics, further studies with larger samples are needed.

Association of RGS2 variants with panic disorder in a Japanese population.

Panic disorder (PD) is a severe and chronic psychiatric disorder with significant genetic components underlying its etiology. The gene regulator of G protein signaling 2 (RGS2) has been reported to be associated with anxiety disorders. To confirm the association of RGS2 with PD, we investigated three single nucleotide polymorphisms (SNPs) of RGS2 (rs10801152, rs4606, and rs1819741) in 677 Japanese PD cases and 460 controls. The SNP rs10801152 was suggestive of an association with PD (allele P = 0.045 adjusted using sex and age as confounding factors). The three‐SNP haplotype was significantly associated with PD (global permutation P = 4 × 10−4). The haplotypes T‐G‐C and T‐C‐T showed significant association and protective effect on PD (T‐G‐C, permutation P = 0.038, OR = 0.80, 95%CI = 0.68–0.95; T‐C‐T, permutation P = 0.004, OR = 0.38, 95%CI = 0.21–0.70). These results provide support for an association of RGS2 with PD in a Japanese population.

Neuronal cell-type specific DNA methylation patterns of the Cacna1c gene

Gene expression of the alpha‐1 subunit of the L‐type voltage‐gated calcium channel, CACNA1C, is known to be complexly regulated. Because CACNA1C is not only a crucial gene in normal brain function but also a promising candidate risk gene for psychiatric disorders such as bipolar disorder and schizophrenia, elucidating the molecular basis of transcriptional regulatory mechanism will be critically important. Here we examined DNA methylation status of CpG islands and a CpG island shore on mouse Cacna1c in neuronal and non‐neuronal nuclei, which were separated with a fluorescent activated cell sorting technique. We found that neurons and non‐neurons showed differential DNA methylation profile on a CpG island shore. This difference was evolutionarily conserved in human neuronal and non‐neuronal nuclei in the prefrontal cortex, suggesting that DNA methylation status on the CpG island shore of Cacna1c may have an important role in transcript regulation.

No association between the brain-derived neurotrophic factor gene and panic disorder in Japanese population.

Panic disorder (PD) is a severe and chronic psychiatric disorder, with significant genetic components in the etiology. Brain-derived neurotrophic factor (BDNF) gene, which has regulatory effects on neurotransmitter systems such as serotonin and dopamine, is a candidate for susceptibility locus of PD. This study investigated three single-nucleotide polymorphisms (SNPs) of BDNF (rs6265 (Val66Met), rs11030104 and rs7103411) in Japanese patients with PD and controls. No significant association was observed between the three SNPs and PD. No association of the Val66Met was consistent with two small studies in Japanese and Chinese populations. We therefore conclude that the BDNF polymorphism may not play a major role in PD in the East Asian populations.