Deep exome sequencing identifies enrichment of deleterious mosaic variants in neurodevelopmental disorder genes and mitochondrial tRNA regions in bipolar disorder.

Bipolar disorder (BD) is a global medical issue, afflicting around 1% of the population with manic and depressive episodes. Despite various genetic studies, the genetic architecture and pathogenesis of BD have not been fully resolved. Besides germline variants, postzygotic mosaic variants are proposed as new candidate mechanisms contributing to BD. Here, we performed extensive deep exome sequencing (DES, ~300×) and validation experiments to investigate the roles of mosaic variants in BD with 235 BD cases (194 probands of trios and 41 single cases) and 39 controls. We found an enrichment of developmental disorder (DD) genes in the genes hit by deleterious mosaic variants in BD (P = 0.000552), including a ClinVar-registered pathogenic variant in ARID2. An enrichment of deleterious mosaic variants was also observed for autism spectrum disorder (ASD) genes (P = 0.000428). The proteins coded by the DD/ASD genes with non-synonymous mosaic variants in BD form more protein-protein interaction than expected, suggesting molecular mechanisms shared with DD/ASD but restricted to a subset of cells in BD. We also found significant enrichment of mitochondrial heteroplasmic variants, another class of mosaic variants, in mitochondrial tRNA genes in BD (P = 0.0102). Among them, recurrent m.3243 A > G variants known as causal for mitochondrial diseases were found in two unrelated BD probands with allele fractions of 5-12%, lower than in mitochondrial diseases. Despite the limitation of using peripheral tissues, our DES investigation supports the possible contribution of deleterious mosaic variants in the nuclear genome responsible for severer phenotypes, such as DD/ASD, to the risk of BD and further demonstrates that the same paradigm can be applied to the mitochondrial genome. These results, as well as the enrichment of heteroplasmic mitochondrial tRNA variants in BD, add a new piece to the understanding of the genetic architecture of BD and provide general insights into the pathological roles of mosaic variants in human diseases.

Usefulness of the autism spectrum quotient (AQ) in screening for autism spectrum disorder and social communication disorder.

BACKGROUND: In the Diagnostic and Statistical Manual and Mental Disorders, Fifth Edition (DSM-5), autism spectrum disorder (ASD) and social (pragmatic) communication disorder (SCD) were described as a new category of psychiatry nosography. SCD involves impairments in social communication and social interaction but not restricted, repetitive patterns of behavior, interests, or activities. The autism spectrum quotient (AQ) was developed to screen for autism tendencies in adults with normal intelligence. However, AQ cutoff scores for screening ASD and SCD in the DSM-5 have not been established. This study examined whether the Japanese version of the AQ (AQ-J) total scores could discriminate between an ASD group, an SCD group, and a neurotypical (NT) group. METHODS: Participants were 127 ASD patients, 52 SCD patients, and 49 NT individuals. Receiver operating characteristic (ROC) analyses were used to examine AQ-J total score cutoff values to distinguish between ASD and NT groups, SCD and NT groups, and ASD and SCD groups. RESULTS: In the ROC analysis for the ASD and NT groups, the area under the curve (AUC) was 0.96, and the optimum cutoff value was 23 points (sensitivity 92.9%, specificity 85.7%). The AUC for the SCD and NT groups was 0.89, and the optimum cutoff value was 22 points (sensitivity 84.6%, specificity 85.7%). The AUC for the ASD and SCD groups was 0.75; the optimum cutoff value was 32 points (sensitivity 67.7%, specificity 71.2%). CONCLUSION: Our findings suggest the usefulness of the AQ-J in screening for ASD and SCD.

Relationships among autistic traits, depression, anxiety, and maternal-infant bonding in postpartum women.

BACKGROUND: Although several studies have found significant relationships between autistic traits and depression/anxiety, the relationships between autistic traits and postpartum depression/anxiety remain unclear. Moreover, few studies have examined the relationships between autistic traits and mother-infant bonding while considering depression or anxiety. METHODS: This study used a cross-sectional data analysis design. Participants were 2692 women who completed the Autism-Spectrum Quotient (AQ), Hospital Anxiety and Depression Scale (HADS), and Mother-to-Infant Bonding Scale (MIBS) at 1 month postpartum. We performed path analysis that included parity, the five AQ subscales (social skills, attention switching, attention to detail, communication, and imagination), both HADS subscales (anxiety and depression), and the two MIBS subscales (lack of affection and anger and rejection). RESULTS: Our path analysis revealed that higher scores for social skills, attention switching, communication, and imagination were associated with higher scores for depression. Higher scores for social skills, attention switching, attention to detail, and communication were associated with higher scores for anxiety. Moreover, difficulties in social skills and imagination were associated with failure of maternal-infant bonding. However, more attention to detail was associated with better maternal-infant bonding. CONCLUSIONS: This study suggests that maternal autistic traits are related to anxiety and depression to a certain degree, but only slightly related to maternal-infant bonding at 1 month postpartum. To improve autistic women's quality of life and that of their newborns, perinatal mental health issues such as anxiety, depression, and maternal-fetal bonding difficulties should be appropriately addressed.

Elevation of EGR1/zif268, a Neural Activity Marker, in the Auditory Cortex of Patients with Schizophrenia and its Animal Model.

The family of epidermal growth factor (EGF) including neuregulin-1 are implicated in the neuropathology of schizophrenia. We established a rat model of schizophrenia by exposing perinatal rats to EGF and reported that the auditory pathophysiological traits of this model such as prepulse inhibition, auditory steady-state response, and mismatch negativity are relevant to those of schizophrenia. We assessed the activation status of the auditory cortex in this model, as well as that in patients with schizophrenia, by monitoring the three neural activity-induced proteins: EGR1 (zif268), c-fos, and Arc. Among the activity markers, protein levels of EGR1 were significantly higher at the adult stage in EGF model rats than those in control rats. The group difference was observed despite an EGF model rat and a control rat being housed together, ruling out the contribution of rat vocalization effects. These changes in EGR1 levels were seen to be specific to the auditory cortex of this model. The increase in EGR1 levels were detectable at the juvenile stage and continued until old ages but displayed a peak immediately after puberty, whereas c-fos and Arc levels were nearly indistinguishable between groups at all ages with an exception of Arc decrease at the juvenile stage. A similar increase in EGR1 levels was observed in the postmortem superior temporal cortex of patients with schizophrenia. The commonality of the EGR1 increase indicates that the EGR1 elevation in the auditory cortex might be one of the molecular signatures of this animal model and schizophrenia associating with hallucination.

Role of insulin-like growth factor 1, sex and corticosteroid hormones in male major depressive disorder.

BACKGROUND: Hormones of the hypothalamic-pituitary-gonadal (HPG), hypothalamic-pituitary-adrenal (HPA), and hypothalamic-pituitary-somatotropic (HPS) axes are potentially involved in major depressive disorder (MDD), but these hormones have not been simultaneously investigated in male patients with MDD. We investigated the association between male MDD symptoms and estradiol, testosterone, cortisol, dehydroepiandrosterone sulfate (DHEAS), and insulin-like growth factor 1 (IGF1). METHODS: Serum estradiol, testosterone, cortisol, DHEAS, and IGF1 levels were measured in 54 male patients with MDD and 37 male controls and were compared with clinical factors. We investigated the associations between hormone levels and Hamilton Depression Rating Scale (HAM-D) scores. The correlations among hormones were also investigated. RESULTS: Patients had significantly lower estradiol levels than controls (22.4 ± 8.4 pg/mL vs. 26.1 ± 8.5 pg/mL, P = 0.040). Serum estradiol levels were negatively correlated with HAM-D scores (P = 0.000094) and positively correlated with Global Assessment of Functioning scores (P = 0.000299). IGF1 levels and the cortisol:DHEAS ratio were higher in patients than in controls (IGF1: 171.5 ± 61.8 ng/mL vs. 144.1 ± 39.2 ng/mL, P = 0.011; cortisol:DHEAS ratio: 0.07 ± 0.05 vs. 0.04 ± 0.02, P = 0.001). DHEAS levels were lower in patients than in controls (227.9 ± 108.4 µg/dL vs. 307.4 ± 131.2 µg/dL, P = 0.002). IGF1, cortisol:DHEAS ratio, and DHEAS were not significantly correlated with HAM-D scores. Cortisol and testosterone levels were not significantly different between patients and controls. Serum estradiol levels were positively correlated with DHEAS levels (P = 0.00062) in patients, but were not significantly correlated with DHEAS levels in controls. CONCLUSION: Estradiol may affect the pathogenesis and severity of patients with MDD in men, and other hormones, such as those in the HPA and HPS axes, may also be involved in male MDD. Additionally, a correlation between estradiol and DHEAS may affect the pathology of MDD in men.

Short daytime napping reduces the risk of cognitive decline in community-dwelling older adults: a 5-year longitudinal study.

BACKGROUND: Beneficial effects of napping on cognition have been suggested in cross-sectional studies. This study aimed to clarify longitudinal associations between cognitive decline and sleep characteristics, particularly daytime napping, over a 5-year period in older adults. METHODS: Study participants were 389 community-dwelling individuals aged ≥65 years living in Ojiya City, Niigata, Japan. Baseline and follow-up examinations were conducted in 2011-2013 and 2016-2018, respectively. Trained nurses visited and interviewed participants to collect the following information at baseline and follow-up: demographic characteristics, disease history, lifestyle habits including bedtime, sleeping hours, and daytime nap duration, and cognitive function. The assessment of cognitive function was performed using the revised Hasegawa's dementia scale (HDS-R), with cognitive decline defined as a change in the HDS-R of ≤ - 3 over 5 years. Odds ratios (ORs) for cognitive decline were calculated using multiple logistic regression analysis. RESULTS: Mean age of participants was 74.6 years (SD 6.4), and the cumulative incidence of cognitive decline was 106/389 (27.3%). The adjusted OR for 1-29 min daytime napping was significantly lower compared to that for no napping (OR = 0.47, 95%CI: 0.23-0.96). Earlier bedtime was associated with cognitive decline (adjusted P for trend = 0.0480). CONCLUSION: Short daytime napping (< 30 min) reduces the risk of cognitive decline over 5 years for community-dwelling older people. A future study will be necessary to confirm the effect of short napping on the reduction of risk for clinically diagnosed dementia.

Perceived parenting before adolescence and parity have direct and indirect effects via depression and anxiety on maternal-infant bonding in the perinatal period.

AIM: This study was aimed towards detecting how perceived parenting practices before adolescence affect maternal-infant bonding in the perinatal period, considering factors such as depression, anxiety, and parity. METHODS: We used the Parental Bonding Instrument (PBI) to examine perceived parenting practices. Participants included 1301 pregnant women who completed the Hospital Anxiety and Depression Scale (HADS) and Mother-to-Infant Bonding Scale (MIBS) at three time points: early pregnancy (approximately 12-15 weeks), late pregnancy (approximately 30-34 weeks) and postpartum (4 weeks after childbirth). We performed a path analysis with factors including parity, PBI subscales (paternal care, paternal overprotection, maternal care and maternal overprotection), HADS and MIBS. RESULTS: Perceived paternal or maternal low care parenting predicted higher HADS and MIBS scores in early pregnancy. Moreover, perceived maternal low care parenting predicted higher HADS scores at postpartum and higher MIBS scores in late pregnancy. Perceived paternal or maternal overprotective parenting predicted higher HADS scores in the pregnancy period. Furthermore, perceived maternal overprotective parenting predicted higher MIBS scores in late pregnancy. Being primipara predicted higher HADS scores at postpartum and higher MIBS scores in early pregnancy and at postpartum. Being multipara predicted higher MIBS scores in late pregnancy. CONCLUSION: This study suggests that perceived negative parenting before adolescence has indirect effects (via anxiety and depression) and direct effects on maternal-infant bonding in the perinatal period.

Lower Prolactin Levels in Patients Treated With Aripiprazole Regardless of Antipsychotic Monopharmacy or Polypharmacy.

BACKGROUND: Hyperprolactinemia is a troublesome adverse effect of antipsychotics. Aripiprazole (ARP), which is one of second-generation antipsychotics, has been reported to lower serum prolactin (PRL) levels. However, few studies have compared the effect of ARP on plasma PRL levels between monopharmacy and polypharmacy with antipsychotics. METHODS: We conducted a large-scale investigation of the physical risk for inpatients with schizophrenia using a questionnaire covering demographic data, the number, dose and type of antipsychotics, and serum PRL levels. RESULTS: Sufficient data to conduct an assessment of the effect on PRL levels between antipsychotic monopharmacy and polypharmacy were obtained from 316 of the inpatients. Serum PRL levels in ARP combination group were lower than non-ARP combination group, regardless of antipsychotic monopharmacy or polypharmacy. CONCLUSIONS: The present study suggests that ARP lowers serum PRL levels regardless of monopharamacy or polypharmacy with antipsychotics.

Hormonal Dynamics Effect of Serum Insulin-Like Growth Factor I and Cortisol/Dehydroepiandrosterone Sulfate Ratio on Symptom Severity of Major Depressive Disorder.

BACKGROUND: Insulin-like growth factor I (IGF-I) is a neurotrophic factor produced by the hypothalamic-pituitary-somatotropic axis and is considered a potential contributor to the pathology of major depressive disorder (MDD). Although it is known that the hypothalamic-pituitary-adrenal axis and cortisol are involved in the pathology of MDD, the association with dehydroepiandrosterone sulfate (DHEAS) remains unclear. The current study sought to clarify the relationship between these hormones and the pathology of MDD. METHODS: Subjects were 91 Japanese patients with a diagnosis of MDD. Serum IGF-I, cortisol, and DHEAS were measured. Samples were taken before breakfast after overnight fasting. Depressive symptoms were assessed using the Hamilton Rating Scale for Depression (HAM-D). RESULTS: Subjects included 59 men and 32 women with an average age of 44.1 ± 13.1 years (mean ± SD). The blood IGF-I level was 152.0 ± 50.0 ng/mL, the cortisol level was 10.1 ± 4.6, and the DHEAS level was 201.3 ± 112.7 µg/dL. The mean HAM-D score was 13.9 ± 9.0. Serum IGF-I levels were not correlated with cortisol. Higher IGF-I, cortisol, and cortisol/DHEAS ratios were associated with higher HAM-D scores (adjusted R = 0.240, P < 0.001), and higher IGF-I and cortisol were associated with higher melancholic or suicide subscores (adjusted R = 0.200, P < 0.001; adjusted R = 0.273, P < 0.001). CONCLUSIONS: Our findings suggest that hormonal dysregulation of the hypothalamic-pituitary-adrenal and hypothalamic-pituitary-somatotropic axes may be related to the symptom severity of MDD, melancholia, and suicide-related factors.

A case report of psychiatric symptoms following direct-acting antiviral and ribavirin combination therapy for chronic hepatitis C in a patient with innate anxiety.

BACKGROUND: Direct-acting antivirals (DAAs) result in a highly sustained virological response rate and better patient tolerance. However, this therapeutic approach may, on rare occasions, give rise to psychiatric symptoms. We describe a case requiring discontinuation of DAA and ribavirin combination therapy due to psychiatric symptoms in a patient with congenital anxious personality traits. The information summarized here will be helpful to physicians treating chronic hepatitis C virus (HCV) infection in patients with underlying psychiatric problems. CASE PRESENTATION: A 57-year-old Japanese woman diagnosed with chronic HCV infection was prescribed DAA and ribavirin combination therapy. She had a history of mild innate anxiety and development of psychiatric symptoms due to interferon (IFN) therapy 8 years prior, which subsided with discontinuation of the therapy. Similar psychiatric symptoms such as enervation, palpitations, an episode of hyperventilation, and consciousness disturbances with myotonia were observed after the administration of the antiviral agents. No abnormal findings related to her symptoms were observed on laboratory or imaging results. Psychiatrists diagnosed the patient as having a somatization disorder induced by the antiviral agents on the basis of innate anxiety. After the discontinuation of therapy, her symptoms gradually improved. CONCLUSIONS: Although DAAs were not causative factors for psychiatric symptoms in phase 3 studies, a post-marketing study reported psychiatric symptoms such as depression in patients with underlying psychiatric problems. Our case suggests psychiatric symptoms might worsen after DAA and ribavirin administration in patients with underlying psychiatric disorders, and therefore, close monitoring is necessary for these patients, especially if they have a history of psychiatric symptoms after IFN.

High-density lipoprotein-cholesterol and antipsychotic medication in overweight inpatients with schizophrenia: post-hoc analysis of a Japanese nationwide survey.

BACKGROUND: Patients with schizophrenia have an increased prevalence of metabolic disturbances compared with the general population. However, the mechanisms underlying the metabolic side effects of antipsychotics are unknown. The aim of the present study was to compare the levels of high-density lipoprotein (HDL)-cholesterol in Japanese schizophrenia patients medicated with olanzapine, risperidone, or aripiprazole monotherapy. METHODS: This study was a post-hoc analysis of a nationwide survey, which included 433 Japanese outpatients with schizophrenia and 674 inpatients. A brief questionnaire was compiled that covered demographic data, systolic blood pressure, diastolic blood pressure, and HDL-cholesterol after reviewing the relevant literature and guidelines. To compare demographic and clinical characteristics, analysis of variance was performed for continuous variables and the chi-square test was performed for categorical variables. For comparisons of HDL-cholesterol levels among the three antipsychotic groups, analysis of covariance was carried out with age, diastolic blood pressure, chlorpromazine-equivalent dosage, and waist circumference as confounding variables after stratification by body mass index (BMI) for each outpatient group and inpatient group. RESULTS: The mean age was 57.9 ± 14.0 years and the mean BMI was 23.4 ± 4.5 kg/m2. HDL-cholesterol levels when stratified by BMI differed significantly (p = 0.019) between the three antipsychotic groups after age, diastolic blood pressure, chlorpromazine-equivalent dosage, and waist circumference in inpatients. A significant difference in HDL-cholesterol levels was only found in the overweight inpatient group, and no significant differences in HDL-cholesterol levels were found among the three antipsychotics for outpatients of all BMI stratifications or inpatients that were underweight or of normal weight. For post-hoc analysis of HDL-cholesterol levels in overweight inpatients, HDL-cholesterol was significantly lower in the olanzapine group than in the aripiprazole group (p = 0.023). CONCLUSIONS: This study reveals a difference in HDL-cholesterol levels in overweight Japanese inpatients with schizophrenia resulting from the use of different antipsychotics. In the post-hoc analysis of HDL-cholesterol levels in overweight inpatients, HDL-cholesterol was significantly lower in the olanzapine group than in the aripiprazole group. Further studies incorporating more detailed evaluations, including diet and physical activity, are needed to clarify the differences in HDL-cholesterol according to antipsychotic use.

Effect of GWAS-Identified Genetic Variants on Maximum QT Interval in Patients With Schizophrenia Receiving Antipsychotic Agents: A 24-Hour Holter ECG Study.

BACKGROUND: Users of antipsychotics (APs) have a risk of sudden cardiac death (SCD). Sudden cardiac death in such patients is thought to be largely due to drug-induced QT prolongation. It has been reported that many subjects with drug-induced torsades de pointes (TdP) have risk alleles associated with subclinical congenital long QT syndrome. METHODS: We investigated the effects of the risk alleles associated with long QT on the QT interval in patients receiving APs using 24-hour Holter electrocardiograms to take into account the circadian fluctuation of QT intervals. We investigated 8 single-nucleotide polymorphisms identified on a GWAS. RESULTS: We found that increased numbers of risk alleles at rs7188697 in NDRG4 and rs11970286 in PLN were the major predictors of an increased maximum QT interval over 24 hours in users of APs. CONCLUSIONS: It could be useful to perform a DNA-based analysis before the initiation of APs to reduce the risk of drug-induced torsades de pointes and SCD.

Sex Differences in the Effect of Atomoxetine on the QT Interval in Adult Patients With Attention-Deficit Hyperactivity Disorder.

BACKGROUND: The effects of atomoxetine on QT in adults remain unclear. In this study, we examined whether the use of atomoxetine to treat attention-deficit hyperactivity disorder in adults is associated with QT prolongation. METHODS: Forty-one subjects with attention-deficit hyperactivity disorder were enrolled in this study. Participants were administered 40, 80, or 120 mg atomoxetine daily and were maintained on their respective dose for at least 2 weeks. We conducted electrocardiographic measurements and blood tests, measuring plasma atomoxetine concentrations after treatment. Electrocardiograms of 24 of the patients were also obtained before atomoxetine treatment. The QT interval was corrected using Bazett (QTcB) and Fridericia (QTcF) correction formulas. RESULTS: In these 24 patients, only the female patients had prolonged QTcB (P = 0.039) after atomoxetine treatment. There was no correlation between plasma atomoxetine concentrations and the corrected QT interval (QTc), or between atomoxetine dosage and the QTc. However, in female patients, there was a significant positive correlation between atomoxetine dosage and the QTcB (r = 0.631, P = 0.012), and there was a marginally significant positive correlation between atomoxetine dosage and the QTcF (r = 0.504, P = 0.055). In male patients, there was no correlation between atomoxetine dosage and the QTcB or QTcF intervals. There was no correlation between plasma atomoxetine concentrations and the QTc in either female or male patients. IMPLICATIONS: Clinicians should exhibit caution when prescribing atomoxetine, particularly for female patients.

Rare FBXO18 variations and risk of schizophrenia: Whole-exome sequencing in two parent-affected offspring trios followed by resequencing and case-control studies.

AIM: Rare variations are suggested to play a role in the genetic etiology of schizophrenia; to further investigate their role, we performed a three-stage study in a Japanese population. METHODS: In the first stage, we performed whole-exome sequencing (WES) of two parent-affected offspring trios. In the second stage, we resequenced the FBXO18 coding region in 96 patients. In the third stage, we tested rare non-synonymous FBXO18 variations for association with schizophrenia in two independent populations comprising a total of 1376 patients and 1496 controls. RESULTS: A rare frameshift variation (L116fsX) in the FBXO18 gene was recurrently identified by WES in both trios. Resequencing FBXO18 coding regions, we detected three rare non-synonymous variations (V15L, L116fsX, and V1006I). However, there were no significant associations between these rare FBXO18 variations and schizophrenia in the case-control study. CONCLUSION: Our present study does not provide evidence for the contribution of rare non-synonymous FBXO18 variations to the genetic etiology of schizophrenia in the Japanese population. However, to draw a definitive conclusion, further studies should be performed using sufficiently large sample sizes.

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

AIM: 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. METHODS: In the first stage, we prioritized rare missense variations using whole-exome sequencing (WES) data from three families, consisting of a proband, an affected sibling, and parents. In the second stage, we performed targeted resequencing of the PDCD11 coding region in 96 patients. In the third stage, we conducted an association study of rare PDCD11 variations with schizophrenia in a total of 1357 patients and 1394 controls. RESULTS: Via WES, we identified two rare missense PDCD11 variations, p.(Asp961Asn) and p.(Val1240Leu), shared by two affected siblings within families. Targeted resequencing of the PDCD11 coding region identified three rare non-synonymous variations: p.(Asp961Asn), p.(Phe1835del), and p.(Arg1837His). The case-control study demonstrated no significant associations between schizophrenia and four rare PDCD11 variations: p.(Asp961Asn), p.(Val1240Leu), p.(Phe1835del), and p.(Arg1837His). CONCLUSION: Our data do not support the role of rare PDCD11 variations in conferring substantial risk for schizophrenia in the Japanese population.

Rural-urban differences in the prevalence of cognitive impairment in independent community-dwelling elderly residents of Ojiya city, Niigata Prefecture, Japan.

BACKGROUND: This study aimed to examine rural-urban differences in the prevalence of cognitive impairment in Japan. METHODS: We targeted 592 residents aged 65 years and older who did not use long-term care insurance services in one rural and two urban areas in Ojiya City, Japan. Of these, 537 (90.7 %) participated in the study. The revised Hasegawa's dementia scale (HDS-R) was used to assess cognitive function, and cognitive impairment was defined as a HDS-R score ≤20. Lifestyle information was obtained through interviews. The prevalence of cognitive impairment was compared according to the levels of predictor variables by odds ratios (ORs) calculated by a logistic regression analysis. RESULTS: Mean age of participants was 75.7 years (SD 7.0). The prevalence of cognitive impairment was 20/239 (8.4 %) in the rural area and 6/298 (2.0 %) in the urban areas, for a total of 26/537 (4.8 %) overall. Men tended to have a higher prevalence of cognitive impairment (P = 0.0628), and age was associated with cognitive impairment (P for trend <0.0001). The rural area had a significantly higher prevalence of cognitive impairment (age- and sex-adjusted OR = 4.04, 95 % CI: 1.54-10.62) than urban areas. This difference was significant after adjusting for other lifestyle factors. CONCLUSIONS: The prevalence of cognitive impairment was higher in the rural area relative to urban areas in Ojiya city. This regional difference suggests the existence of potentially modifiable factors other than lifestyle in relation to cognitive impairment.

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. © 2016 Wiley Periodicals, Inc.

GIPR Gene Polymorphism and Weight Gain in Patients With Schizophrenia Treated With Olanzapine.

Association between gastric inhibitory polypeptide receptor polymorphism, rs10423928, and body mass index in olanzapine-treated schizophrenia was examined. Body mass index change for the A/T+A/A genotypes was significantly higher than that for the T/T genotype. rs10423928 may predict weight gain in schizophrenia.