Shared genetic components between metabolic syndrome and schizophrenia: Genetic correlation using multipopulation data sets.

AIM: The genetic relationship between schizophrenia (SCZ) and other nonpsychiatric disorders remains largely unknown. We examined the shared genetic components between these disorders based on multipopulation data sets. METHODS: We used two data sets for East Asian (EAS) and European (EUR) samples. SCZ data was based on the Psychiatric Genomics Consortium Asia with our own genome-wide association study for EAS and Psychiatric Genomics Consortium for EUR. Nonpsychiatric data (20 binary traits [mainly nonpsychiatric complex disorders] and 34 quantitative traits [mainly laboratory examinations and physical characteristics]) were obtained from Biobank Japan and UK Biobank for EAS and EUR samples, respectively. To evaluate genetic correlation, linkage disequilibrium score regression analysis was utilized with further meta-analysis for each result from EAS and EUR samples to obtain robust evidence. Subsequent mendelian randomization analysis was also included to examine the causal effect. RESULTS: A significant genetic correlation between SCZ and several metabolic syndrome (MetS) traits was detected in the combined samples (meta-analysis between EAS and EUR data) (body mass index [rg  = -0.10, q-value = 1.0 × 10-9 ], high-density-lipoprotein cholesterol [rg  = 0.072, q-value = 2.9 × 10-3 ], blood sugar [rg  = -0.068, q-value = 1.4 × 10-2 ], triglycerides [rg  = -0.052, q-value = 2.4 × 10-2 ], systolic blood pressure [rg  = -0.054, q-value = 3.5 × 10-2 ], and C-reactive protein [rg  = -0.076, q-value = 7.8 × 10-5 ]. However, no causal relationship on SCZ susceptibility was detected for these traits based on the mendelian randomization analysis. CONCLUSION: Our results indicate shared genetic components between SCZ and MetS traits and C-reactive protein. Specifically, we found it interesting that the correlation between MetS traits and SCZ was the opposite of that expected from clinical studies: this genetic study suggests that SCZ susceptibility was associated with reduced MetS. This implied that MetS in patients with SCZ was not associated with genetic components but with environmental factors, including antipsychotics, lifestyle changes, poor diet, lack of exercise, and living conditions.

Cost effectiveness of pharmacogenetic-guided clozapine administration based on risk of HLA variants in Japan and the UK.

Pharmacogenetics/pharmacogenomics have enabled the detection of risk of human leukocyte antigen (HLA) variants for clozapine-induced agranulocytosis/granulocytopenia (CIAG). To apply this evidence to the clinical setting, we compared the cost-effectiveness of the proposed "HLA-guided treatment schedule" and the "current schedule" being used in Japan and the United Kingdom (UK) (absolute neutrophil count (ANC) cutoff at 1500/mm3); in the "HLA-guided treatment schedules," we considered a situation wherein the HLA test performed before clozapine initiation could provide "a priori information" by detecting patients harboring risk of HLA variants (HLA-B*59:01 and "HLA-B 158T/HLA-DQB1 126Q" for Japanese and Caucasian populations, respectively), a part of whom can then avoid CIAG onset (assumed 30% "prevention rate"). For the primary analysis, we estimated the incremental cost-effectiveness ratio (ICER) of "HLA-guided treatment schedule" and "current schedule" used in Japan and the UK, using a Markov model to calculate the cost and quality-adjusted life years (QALYs) over a 10-year time period. Furthermore, as an explorative analysis, we simulated several situations with various ANC cutoffs (1000/mm3 and 500/mm3) and plotted the cost/QALYs for each option to identify the best, or estimate the next best candidate option applicable in actual clinical settings. The primary probabilistic analysis showed that the "HLA-guided treatment schedule" was more cost effective than the "current schedule"; the ICER was £20,995 and £21,373 for the Japanese and the UK populations, respectively. Additional simulation revealed that the treatment option of ANC cutoff at 500/mm3 without HLA screening was the most cost-effective option; however, several options may be candidates to break away from the "current schedule" of ANC cutoff at 1500/mm3. Owing to its cost-effectiveness, we propose such pharmacogenetic-guided/pharmacogenomic-guided clozapine treatment for use in the real-world setting, which provides key information for optimization of clinical guidelines for high-risk patients for gradual change of clozapine treatment schedule under the safety consideration.

Effect of a brief cognitive behavioral program on depressive symptoms among newly licensed registered nurses: An observational study.

Depressive symptoms are a serious problem in workplaces. Hospital staff members, such as newly licensed registered nurses (NLRNs), are at particularly increased risk of these symptoms owing to their limited experience. Previous studies have shown that a brief program-based cognitive behavioral therapy program (CBP) can offer effective treatment. Here, we conducted a longitudinal observational study of 683 NLRNs (CBP group, n = 522; no-CBP group, n = 181) over a period of 1 year (six times surveys were done during this period). Outcomes were assessed on the basis of surveys that covered the Beck Depression Inventory-I (BDI). The independent variables were CBP attendance (CBP was conducted 3 months after starting work), personality traits, personal stressful life events, workplace adversity, and pre-CBP change in BDI in the 3 months before CBP (ΔBDIpre-CBP). All factors were included in Cox proportional hazards models with time-dependent covariates for depressive symptoms (BDI ≥10), and we reported hazard ratios (HRs). Based on this analysis, we detected that CBP was significantly associated with benefit for depressive symptoms in all NLRNs (Puncorrected = 0.0137, HR = 0.902). To identify who benefitted most from CBP, we conducted a subgroup analysis based on the change in BDI before CBP (ΔBDIpre-CBP). The strongest association was when BDI scores were low after starting work and increased before CBP (Puncorrected = 0.00627, HR = 0.616). These results are consistent with previous findings, and indicate that CBP may benefit the mental health of NLRNs. Furthermore, selective prevention based on the pattern of BDI change over time may be important in identifying who should be offered CBP first. Although CBP is generally effective for all nurses, such a selective approach may be most appropriate where cost-effectiveness is a prominent concern.

Polygenic risk scores in schizophrenia with clinically significant copy number variants.

AIMS: Recent studies have revealed that the interplay between polygenic risk scores (PRS) and large copy number variants (CNV; >500kb) is essential for the etiology of schizophrenia (SCZ). To replicate previous findings, including those for smaller CNV (>10kb), the PRS between SCZ patients with and without CNV were compared. METHODS: The PRS were calculated for 724 patients with SCZ and 1178 healthy controls (HC), genotyped using array-based comparative genomic hybridization and single nucleotide polymorphisms chips, and comparisons were made between cases and HC, or between subjects with and without 'clinically significant' CNV. RESULTS: First, we replicated the higher PRS in patients with SCZ compared to that in HC (without taking into account the CNV). For clinically significant CNV, as defined by the American College of Medical Genetics ('pathogenic' and 'uncertain clinical significance, likely pathogenic' CNV), 66 patients with SCZ carried clinically significant CNV, whereas 658 SCZ patients had no such CNV. In the comparison of PRS between cases with/without the CNV, despite no significant difference in PRS, significant enrichment of the well-established risk CNV (22q11.2 deletion and 47,XXY/47,XXX) was observed in the lowest decile of PRS in SCZ patients with the CNV. CONCLUSION: Although the present study failed to replicate the significant difference in PRS between SCZ patients with and without clinically significant CNV, SCZ patients with well-established risk CNV tended to have a lower PRS. Therefore, we speculate that the CNV in SCZ patients with lower PRS may contain 'genuine' risk; PRS is a possible tool for prioritizing clinically significant CNV because the power of the CNV association analysis is limited due to their rarity.

Genome-Wide Association Study Detected Novel Susceptibility Genes for Schizophrenia and Shared Trans-Populations/Diseases Genetic Effect.

Genome-wide association studies (GWASs) have identified >100 susceptibility loci for schizophrenia (SCZ) and demonstrated that SCZ is a polygenic disorder determined by numerous genetic variants but with small effect size. We conducted a GWAS in the Japanese (JPN) population (a) to detect novel SCZ-susceptibility genes and (b) to examine the shared genetic risk of SCZ across (East Asian [EAS] and European [EUR]) populations and/or that of trans-diseases (SCZ, bipolar disorder [BD], and major depressive disorder [MDD]) within EAS and between EAS and EUR (trans-diseases/populations). Among the discovery GWAS subjects (JPN-SCZ GWAS: 1940 SCZ cases and 7408 controls) and replication dataset (4071 SCZ cases and 54479 controls), both comprising JPN populations, 3 novel susceptibility loci for SCZ were identified: SPHKAP (Pbest = 4.1 × 10-10), SLC38A3 (Pbest = 5.7 × 10-10), and CABP1-ACADS (Pbest = 9.8 × 10-9). Subsequent meta-analysis between our samples and those of the Psychiatric GWAS Consortium (PGC; EUR samples) and another study detected 12 additional susceptibility loci. Polygenic risk score (PRS) prediction revealed a shared genetic risk of SCZ across populations (Pbest = 4.0 × 10-11) and between SCZ and BD in the JPN population (P ~ 10-40); however, a lower variance-explained was noted between JPN-SCZ GWAS and PGC-BD or MDD within/across populations. Genetic correlation analysis supported the PRS results; the genetic correlation between JPN-SCZ and PGC-SCZ was ρ = 0.58, whereas a similar/lower correlation was observed between the trans-diseases (JPN-SCZ vs JPN-BD/EAS-MDD, rg = 0.56/0.29) or trans-diseases/populations (JPN-SCZ vs PGC-BD/MDD, ρ = 0.38/0.12). In conclusion, (a) Fifteen novel loci are possible susceptibility genes for SCZ and (b) SCZ "risk" effect is shared with other psychiatric disorders even across populations.

Risk factors and clinical characteristics of the depressive state induced by pegylated interferon therapy in patients with hepatitis C virus infection: A prospective study.

AIM: Pegylated interferon (PegIFN) therapies for hepatitis C virus (HCV) infection often induce a depressive state. This study aimed to identify the risk factors for and clinical characteristics of PegIFN-induced depressive state. METHODS: Sixty-nine subjects with HCV who received PegIFN therapy were enrolled. Before beginning therapy, all subjects were evaluated using the Neuroticism-Extraversion-Openness Five-Factor Inventory and the List of Threatening Events Questionnaire. Beck Depression Inventory (BDI) scores were also evaluated at baseline, 2-4 weeks after initiating therapy, and every 4 weeks thereafter. RESULTS: During the study, 18 subjects (24.3%) developed a depressive state (BDI ≥ 10). A bimodal peak of onset was observed during the early (2-8 weeks) and late (after 20 weeks) therapy phases. Moreover, we observed that baseline BDI scores (odds ratio [OR] = 1.40, P = 0.0104) and neuroticism (OR = 1.14, P = 0.0275) were significant risk factors for developing a depressive state. To determine the specific characteristics of this condition, we compared the BDI subscales between the 'PegIFN-induced' and 'general' depressive state reported previously. We found that the score at 'somatic symptoms' was higher in the 'PegIFN-induced' group. CONCLUSION: Our results indicate the following: (i) PegIFN-induced depressive state most frequently develops during the first 8 weeks of therapy; (ii) baseline BDI and neuroticism scores are risk factors for PegIFN-induced depressive state; and (iii) the core symptoms of PegIFN-induced depressive state are different from those of 'general' depression.

Pharmacogenomic Study of Clozapine-Induced Agranulocytosis/Granulocytopenia in a Japanese Population.

BACKGROUND: Clozapine-induced agranulocytosis (CIA)/clozapine-induced granulocytopenia (CIG) (CIAG) is a life-threatening event for schizophrenic subjects treated with clozapine. METHODS: To examine the genetic factor for CIAG, a genome-wide pharmacogenomic analysis was conducted using 50 subjects with CIAG and 2905 control subjects. RESULTS: We identified a significant association in the human leukocyte antigen (HLA) region (rs1800625, p = 3.46 × 10(-9), odds ratio [OR] = 3.8); therefore, subsequent HLA typing was performed. We detected a significant association of HLA-B*59:01 with CIAG (p = 3.81 × 10(-8), OR = 10.7) and confirmed this association by comparing with an independent clozapine-tolerant control group (n = 380, p = 2.97 × 10(-5), OR = 6.3). As we observed that the OR of CIA (OR: 9.3~15.8) was approximately double that in CIG (OR: 4.4~7.4), we hypothesized that the CIG subjects were a mixed population of those who potentially would develop CIA and those who would not develop CIA (non-CIA). This hypothesis allowed the proportion of the CIG who were non-CIA to be calculated, enabling us to estimate the positive predictive value of the nonrisk allele on non-CIA in CIG subjects. Assuming this model, we estimated that 1) ~50% of CIG subjects would be non-CIA; and 2) ~60% of the CIG subjects without the risk allele would be non-CIA and therefore not expected to develop CIA. CONCLUSIONS: Our results suggest that HLA-B*59:01 is a risk factor for CIAG in the Japanese population. Furthermore, if our model is true, the results suggest that rechallenging certain CIG subjects with clozapine may not be always contraindicated.

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.

A genetic variant in 12q13, a possible risk factor for bipolar disorder, is associated with depressive state, accounting for stressful life events.

Genome-wide association studies (GWASs) have identified a number of susceptibility genes for schizophrenia (SCZ) and bipolar disorder (BD). However, the identification of risk genes for major depressive disorder (MDD) has been unsuccessful because the etiology of MDD is more influenced by environmental factors; thus, gene-environment (G × E) interactions are important, such as interplay with stressful life events (SLEs). We assessed the G×E interactions and main effects of genes targeting depressive symptoms. Using a case-control design, 922 hospital staff members were evaluated for depressive symptoms according to Beck Depressive Inventory (BDI; "depression" and "control" groups were classified by scores of 10 in the BDI test), SLEs, and personality. A total of sixty-three genetic variants were selected on the basis of previous GWASs of MDD, SCZ, and BD as well as candidate-gene (SLC6A4, BDNF, DBH, and FKBP5) studies. Logistic regression analysis revealed a marginally significant interaction (genetic variant × SLE) at rs4523957 (P uncorrected = 0.0034) with depression and a significant association of single nucleotide polymorphism identified from evidence of BD GWAS (rs7296288, downstream of DHH at 12q13.1) with depression as the main effect (P uncorrected = 9.4 × 10(-4), P corrected = 0.0424). We also found that SLEs had a larger impact on depression (odds ratio ∼ 3), as reported previously. These results suggest that DHH plays a possible role in depression etiology; however, variants from MDD or SCZ GWAS evidence or candidate genes showed no significant associations or minimal effects of interactions with SLEs on depression.

Replication and cross-phenotype study based upon schizophrenia GWASs data in the Japanese population: support for association of MHC region with psychosis.

Recent genome-wide association studies (GWASs) of schizophrenia (SCZ) identified several susceptibility genes and suggested shared genetic components between SCZ and bipolar disorder (BD). We conducted a genetic association study of single nucleotide polymorphisms (SNPs) selected according to previous SCZ GWAS targeting psychotic disorders (SCZ and BD) in the Japanese population. Fifty-one SNPs were analyzed in a two-stage design using first-set screening samples (all SNPs: 1,032 SCZ, 1,012 BD, and 993 controls) and second-set replication samples ("significant" SNPs in the first-set screening analysis: 1,808 SCZ, 821 BD, and 2,321 controls). We assessed allelic associations between the selected SNPs and the three phenotypes (SCZ, BD, and "psychosis" [SCZ + BD]). Nine SNPs revealed nominal association signals for all comparisons (P(uncorrected) < 0.05), of which two SNPs located in the major histocompatibility complex region (rs7759855 in zinc finger and SCAN domain containing 31 [ZSCAN31] and rs1736913 in HLA-F antisense RNA1 [HLA-F-AS1]) were further assessed in the second-set replication samples. The associations were confirmed for rs7759855 (P(corrected) = 0.026 for psychosis; P(corrected) = 0.032 for SCZ), although the direction of effect was opposite to that in the original GWAS of the Chinese population. Finally, a meta-analysis was conducted using our two samples and using our data and data from Psychiatric GWAS Consortium (PGC), which have shown the same direction of effect. SNP in ZSCAN31 (rs7759855) had the strongest association with the phenotypes (best P = 6.8 × 10(-5) for psychosis: present plus PGC results). These data support shared risk SNPs between SCZ and BD in the Japanese population and association between MHC and psychosis.