Hirofumi Igeta

Interleukin 1 beta gene and risk of schizophrenia: detailed case-control and family-based studies and an updated meta-analysis.

Interleukin‐1 beta (IL‐1β) has been implicated in the pathophysiology of schizophrenia. To assess whether the IL1B gene confers increased susceptibility to schizophrenia, we conducted case–control and family‐based studies and an updated meta‐analysis.

Deterioration in donepezil-induced PR prolongation after a coadministration of memantine in a patient with Alzheimer's disease

The side effects and interaction of memantine and donepezil hydrochloride when used concomitantly are currently unknown. We encountered a case of a 77-year-old female with Alzheimers disease in which the concomitant use of memantine exacerbated the prolonged electrocardiogram PR interval which appeared while donepezil hydrochloride was being orally administered. In terms of the cardiac circulation system side effects caused by donepezil hydrochloride and memantine, bradycardia has been reported. However, clinicians should be also aware of PR prolongation associated with the concomitant use of donepezil and memantine.

Rare UNC13B variations and risk of schizophrenia: Whole-exome sequencing in a multiplex family and follow-up resequencing and a case-control study.

Rare genomic variations inherited in multiplex schizophrenia families are suggested to play a role in the genetic etiology of the disease. To identify rare variations with large effects on the risk of developing schizophrenia, we performed whole‐exome sequencing (WES) in two affected and one unaffected individual of a multiplex family with 10 affected individuals. We also performed follow‐up resequencing of the unc‐13 homolog B (Caenorhabditis elegans) (UNC13B) gene, a potential risk gene identified by WES, in the multiplex family and undertook a case–control study to investigate association between UNC13B and schizophrenia. UNC13B coding regions (39 exons) from 15 individuals of the multiplex family and 111 affected offspring for whom parental DNA samples were available were resequenced. Rare missense UNC13B variations identified by resequencing were further tested for association with schizophrenia in two independent case–control populations comprising a total of 1,753 patients and 1,602 controls. A rare missense variation (V1525M) in UNC13B was identified by WES in the multiplex family; this variation was present in five of six affected individuals, but not in eight unaffected individuals or one individual of unknown disease status. Resequencing UNC13B coding regions identified five rare missense variations (T103M, M813T, P1349T, I1362T, and V1525M). In the case–control study, there was no significant association between rare missense UNC13B variations and schizophrenia, although single‐variant meta‐analysis indicated that M813T was nominally associated with schizophrenia. These results do not support a contribution of rare missense UNC13B variations to the genetic etiology of schizophrenia in the Japanese population.

Rare heterozygous truncating variations and risk of autism spectrum disorder: Whole-exome sequencing of a multiplex family and follow-up study in a Japanese population

Rare heterozygous truncating variations in multiplex families with autism spectrum disorder (ASD) are suggested to play a major role in the genetic etiology of ASD. To further investigate the role of rare heterozygous truncating variations, we performed whole‐exome sequencing (WES) in a multiplex ASD family with four affected individuals (two siblings and two maternal cousins), and a follow‐up case–control study in a Japanese population.

Novel Rare Missense Variations and Risk of Autism Spectrum Disorder: Whole-Exome Sequencing in Two Families with Affected Siblings and a Two-Stage Follow-Up Study in a Japanese Population

Rare inherited variations in multiplex families with autism spectrum disorder (ASD) are suggested to play a major role in the genetic etiology of ASD. To further investigate the role of rare inherited variations, we performed whole-exome sequencing (WES) in two families, each with three affected siblings. We also performed a two-stage follow-up case-control study in a Japanese population. WES of the six affected siblings identified six novel rare missense variations. Among these variations, CLN8 R24H was inherited in one family by three affected siblings from an affected father and thus co-segregated with ASD. In the first stage of the follow-up study, we genotyped the six novel rare missense variations identified by WES in 241 patients and 667 controls (the Niigata sample). Only CLN8 R24H had higher mutant allele frequencies in patients (1/482) compared with controls (1/1334). In the second stage, this variation was further genotyped, yet was not detected in a sample of 309 patients and 350 controls (the Nagoya sample). In the combined Niigata and Nagoya samples, there was no significant association (odds ratio = 1.8, 95% confidence interval = 0.1–29.6). These results suggest that CLN8 R24H plays a role in the genetic etiology of ASD, at least in a subset of ASD patients.

Cardiovascular pharmacodynamics of donepezil hydrochloride on the PR and QT intervals in patients with dementia

Although several case reports suggested that donepezil hydrochloride can induce bradycardia or atrioventricular block, the details remain unclear. We implemented a study of the impact of donepezil hydrochloride administration on PR, RR, and QT intervals.

Rare truncating variations and risk of schizophrenia: Whole-exome sequencing in three families with affected siblings and a three-stage follow-up study in a Japanese population

Rare inherited variations in multiplex families with schizophrenia are suggested to play a role in the genetic etiology of schizophrenia. To further investigate the role of rare inherited variations, we performed whole-exome sequencing (WES) in three families, each with two affected siblings. We also performed a three-stage follow-up case-control study in a Japanese population with a total of 2617 patients and 2396 controls. WES identified 15 rare truncating variations that were variously present in the two affected siblings in each family. These variations did not necessarily segregate with schizophrenia within families, and they were different in each family. In the follow-up study, four variations (NWD1 W169X, LCORL R7fsX53, CAMK2B L497fsX497, and C9orf89 Q102X) had a higher mutant allele frequency in patients compared with controls, although these associations were not significant in the combined population, which comprised the first-, second- and third-stage populations. These results do not support a contribution of the rare truncating variations identified in the three families to the genetic etiology of schizophrenia.

Whole-exome sequencing in a family with a monozygotic twin pair concordant for autism spectrum disorder and a follow-up study

Two truncating variations (WDR90 V1125fs and EFCAB5 L1210fs), identified by whole-exome sequencing in a family with a monozygotic twin pair concordant for autism spectrum disorder (ASD), were not detected in 257 ASD patients, 677 schizophrenia patients or 667 controls in a follow-up study. Thus, these variations were exclusively identified in the family, suggesting that rare truncating variations may have a role in the genetic etiology of ASD, at least in a subset of ASD patients.

A rare MIR138-2 gene variation is associated with schizophrenia in a Japanese population

MicroRNAs (miRNAs) are small non-coding RNAs, and may be involved in the neurobiological mechanisms underlying schizophrenia (Beveridge and Cairns, 2012). To determine if four rare variations (in MIR30C2, MIR138-2, MIR217, and MIR302A) identified by resequencing of 173 miRNA genes in 96 Japanese individuals (Iwai and Naraba, 2005) are associated with schizophrenia, we performed case-control studies using two independent Japanese samples. The present study was approved by the Ethics Committee of Genetics at the Niigata University School of Medicine, and the Ethical Committee for Genetic Studies at Kobe University Graduate School of Medicine. Written informed consent was obtained from all participants. The Niigata sample comprised 678 patients with schizophrenia (363 men and 315 women; mean age 39.6713.8 years) and 667 control individuals (341 men and 326 women; mean age 38.3710.8 years). The Kobe sample comprised 660 patients with schizophrenia (344 men and 316 women; mean age 52.6714.9 years) and 734 control individuals (345 men and 389 women; mean age 54.3718.6 years). Psychiatric assessment of each participant was conducted, as previously described (Watanabe et al., 2006; Yoshida et al., 2012). We genotyped four rare single nucleotide variations (SNVs) in MIR30C2 (chr6: 72086719G4T), MIR138-2 (chr16: 56892431G4 T; rs139365823),MIR217 (chr2: 56210123A4T), andMIR302A (chr4: 113569394C4T), using the TaqMan 50-exonuclease assay (Applied Biosystems, Foster City, CA). Allelic association was determined using Fisher0s exact test. In the Niigata sample, the mutated T allele frequency of rs139365823 in MIR138-2 was less in patients than in controls, with a marginal trend toward significance (P1⁄40.05; Table 1). SNVs in MIR217 and MIR302A were monomorphic and therefore excluded from further analysis. In the Kobe sample, the T allele frequency of rs139365823 was significantly lower in patients than in controls (P1⁄40.02; Table 1). When we combined both population samples, there was a significant association between rs139365823 and schizophrenia (odds ratio1⁄40.32; 95% confidence interval1⁄40.15– 0.71; P1⁄40.003; Table 1). Our case-control studies using two independent Japanese samples show that the mutated T allele frequency of rs139365823 in MIR138-2 is significantly lower in patients than in controls. MiRNA138 expression levels are increased in the superior temporal gyrus (Beveridge et al., 2010) and decreased in dorsolateral prefrontal cortex, of patients with schizophrenia (Moreau et al., 2011). Based on these findings, we suggest that rs139365823 may be protective against schizophrenia by altering processing of primary to mature miRNA-138-2. However, the functional implications of rs139365823 are still unclear and should be clarified in future studies. The association between schizophrenia and the SNV identified in MIR30C2 is in opposing directions in the two population samples. This is due to differences in T allele frequencies of the SNV between controls from the Niigata and Kobe samples (0.007 and 0.0007, respectively). To identify any typing errors, we performed direct sequencing in 20 individuals, confirming the genotypes obtained using TaqMan. Thus, the likelihood of genotyping errors appears low. Because both Niigata and Kobe samples were collected from the main island of Japan, we speculate that population stratification is minimal.

Rare PDCD11 variations are not associated with risk of schizophrenia in Japan

Rare gene variations are thought to confer substantial risk for schizophrenia. We performed a three‐stage study to identify rare variations that have a strong impact on the risk of developing schizophrenia.