Discrimination between healthy participants and people with panic disorder based on polygenic scores for psychiatric disorders and for intermediate phenotypes using machine learning.

OBJECTIVE: Panic disorder is a modestly heritable condition. Currently, diagnosis is based only on clinical symptoms; identifying objective biomarkers and a more reliable diagnostic procedure is desirable. We investigated whether people with panic disorder can be reliably diagnosed utilizing combinations of multiple polygenic scores for psychiatric disorders and their intermediate phenotypes, compared with single polygenic score approaches, by applying specific machine learning techniques. METHODS: Polygenic scores for 48 psychiatric disorders and intermediate phenotypes based on large-scale genome-wide association studies (n = 7556-1,131,881) were calculated for people with panic disorder (n = 718) and healthy controls (n = 1717). Discrimination between people with panic disorder and healthy controls was based on the 48 polygenic scores using five methods for classification: logistic regression, neural networks, quadratic discriminant analysis, random forests and a support vector machine. Differences in discrimination accuracy (area under the curve) due to an increased number of polygenic score combinations and differences in the accuracy across five classifiers were investigated. RESULTS: All five classifiers performed relatively well for distinguishing people with panic disorder from healthy controls by increasing the number of polygenic scores. Of the 48 polygenic scores, the polygenic score for anxiety UK Biobank was the most useful for discrimination by the classifiers. In combinations of two or three polygenic scores, the polygenic score for anxiety UK Biobank was included as one of polygenic scores in all classifiers. When all 48 polygenic scores were used in combination, the greatest areas under the curve significantly differed among the five classifiers. Support vector machine and logistic regression had higher accuracy than quadratic discriminant analysis and random forests. For each classifier, the greatest area under the curve was 0.600 ± 0.030 for logistic regression (polygenic score combinations N = 14), 0.591 ± 0.039 for neural networks (N = 9), 0.603 ± 0.033 for quadratic discriminant analysis (N = 10), 0.572 ± 0.039 for random forests (N = 25) and 0.617 ± 0.041 for support vector machine (N = 11). The greatest areas under the curve at the best polygenic score combination significantly differed among the five classifiers. Random forests had the lowest accuracy among classifiers. Support vector machine had higher accuracy than neural networks. CONCLUSIONS: These findings suggest that increasing the number of polygenic score combinations up to approximately 10 effectively improved the discrimination accuracy and that support vector machine exhibited greater accuracy among classifiers. However, the discrimination accuracy for panic disorder, when based solely on polygenic score combinations, was found to be modest.

Longitudinal relationships of psychotic-like experiences with suicidal ideation and self-harm in adolescents.

Research in adolescents suggests associations between psychotic-like experiences (PLEs) and self-injurious thoughts and behaviors (SITBs), but insights into their temporal relationship, which may inform prediction, have been limited. Psychological distress (PD; symptoms of depression and anxiety) has been related to both PLEs and SITBs, and may modulate this relationship. Given that PLEs have been linked to the development of several mental disorders, and the relationships between SITBs and suicide, it is important to better understand their relationship. The present study sought to investigate these factors using a longitudinal school-based design. Adolescents (n = 1685, ages 12-18) completed annual self-report assessments (6 time points) on PLEs, SITBs (suicidal ideation (SI) and self-harm (SH)), as well as PD. The longitudinal associations between PLEs and SITBs were analyzed, employing two cross-lagged panel models (CLPMs), with and without adjustment for PD. Unadjusted CLPMs revealed significant bidirectional temporal associations between PLEs and SITBs (both SI and SH), suggesting that PLEs both predicted and were predicted by SITBs. When adjusting for PD, the effect of SI on PLEs remained significant, but not PLEs on SI; bidirectional associations between PLEs and SH also remained significant. A bidirectional longitudinal relationship where both PLEs and SITBs can precede (and perhaps predict) each other was suggested in adolescents. PD may play a particular role in situations where PLEs are followed by SI. Heightened awareness about relationships between these phenotypes may be an important step toward facilitating timely interventions for both mental disorders and suicide.

A loss-of-function variant in SUV39H2 identified in autism-spectrum disorder causes altered H3K9 trimethylation and dysregulation of protocadherin ß-cluster genes in the developing brain.

Recent evidence has documented the potential roles of histone-modifying enzymes in autism-spectrum disorder (ASD). Aberrant histone H3 lysine 9 (H3K9) dimethylation resulting from genetic variants in histone methyltransferases is known for neurodevelopmental and behavioral anomalies. However, a systematic examination of H3K9 methylation dynamics in ASD is lacking. Here we resequenced nine genes for histone methyltransferases and demethylases involved in H3K9 methylation in individuals with ASD and healthy controls using targeted next-generation sequencing. We identified a novel rare variant (A211S) in the SUV39H2, which was predicted to be deleterious. The variant showed strongly reduced histone methyltransferase activity in vitro. In silico analysis showed that the variant destabilizes the hydrophobic core and allosterically affects the enzyme activity. The Suv39h2-KO mice displayed hyperactivity and reduced behavioral flexibility in learning the tasks that required complex behavioral adaptation, which is relevant for ASD. The Suv39h2 deficit evoked an elevated expression of a subset of protocadherin ß (Pcdhb) cluster genes in the embryonic brain, which is attributable to the loss of H3K9 trimethylation (me3) at the gene promoters. Reduced H3K9me3 persisted in the cerebellum of Suv39h2-deficient mice to an adult stage. Congruently, reduced expression of SUV39H1 and SUV39H2 in the postmortem brain samples of ASD individuals was observed, underscoring the role of H3K9me3 deficiency in ASD etiology. The present study provides direct evidence for the role of SUV39H2 in ASD and suggests a molecular cascade of SUV39H2 dysfunction leading to H3K9me3 deficiency followed by an untimely, elevated expression of Pcdhb cluster genes during early neurodevelopment.

Influence of perceived trauma on the cognitive processing model of posttraumatic growth among university students.

This study examined whether perceiving an event as a trauma influenced a cognitive processing model explaining posttraumatic growth (PTG). A cross-sectional questionnaire survey was conducted with 311 university students from eight universities in Japan. The participants provided information about the most stressful event they had experienced and completed the expanded version of the PTG Inventory, Core Belief Inventory, Event Related Rumination Inventory, and Cognitive and Emotional Processing from Disclosure Inventory. A multi-group structural equation modeling was conducted by dividing the participants into two groups depending on whether they identified the most stressful event as a trauma. The model with no constraint showed a good fit. The model with partial constraint showed a better fit than the models with no constraint or full constraint. The difference of the model was seen as a covariance between the Event Related Rumination Inventory and the Cognitive and Emotional Processing from Disclosure Inventory. The results demonstrated configural invariance and partial metric invariance. This indicated that PTG would be recognized irrespective of whether the event was perceived as a trauma. This study also indicated that different factors out of the model could be associated with the ruminative process and disclosure process. The importance of focusing on the process of PTG, regardless of an individual's perception of the event, was emphasized, especially for factors related to rumination and disclosure.

Association of Serotonin Transporter Gene (5-HTTLPR/rs25531) Polymorphism with Comorbidities of Panic Disorder.

INTRODUCTION: Panic disorder (PD) has many comorbidities such as depression, bipolar disorder (BPD), and agoraphobia (AG). PD is a moderately heritable anxiety disorder whose pathogenesis is not well understood. Recently, a tri-allelic serotonin transporter (5-HTTLPR/rs25531) polymorphism was reported to be more sensitive to personality traits compared to the bi-allelic 5-HTTLPR polymorphism. We hypothesized that the 5-HTTLPR/rs25531 polymorphism may lead to a pathological anxious state depending on the presence or absence of a comorbidity in PD. METHODS: In this study, we investigated the relationship between comorbidities in PD and tri-allelic 5-HTTLPR polymorphisms. A total of 515 patients with PD (148 males, 367 females) were genotyped, and the Revised NEO Personality Inventory as well as anxiety-related psychological tests were administered. Depression, BPD, and AG were diagnosed as comorbidities. RESULTS: For the tri-allele 5-HTTLPR genotype, a significant interaction effect was found between openness to experience and comorbid depression. Examination of the interaction between AG and the tri-allelic 5-HTTLPR genotype revealed that L' allele carriers are associated with higher trait anxiety than the S'S' genotype group in PD without AG. CONCLUSION: Some anxiety and personality traits can be characterized by the tri-allelic gene effect of 5-HTTLPR. These results suggest that tri-allelic 5-HTTLPR genotypes have genetic effects on the presence of comorbidities of PD.

A survey of mental health literacy in Japanese high school teachers.

BACKGROUND: School teachers are well-positioned to recognize mental health problems in their students and to help them seek appropriate help. Therefore, teachers need to have high levels of mental health literacy (MHL). In East Asia, however, few studies have examined MHL levels in teachers. In this study, MHL levels were investigated in Japanese teachers. METHODS: Teachers (n = 665) from 27 Japanese high schools answered a self-administered questionnaire which assessed (a) knowledge about mental health/illnesses, (b) correct recognition of specific illnesses (depression, schizophrenia and panic disorder), (c) confidence in helping students with depressive symptoms, and (d) confidence in teaching mental health knowledge to students. RESULTS: The average proportion of correct answers to the knowledge questions (n = 20) was 58.1%. The proportion of those who correctly answered about the presence of a sharp increase of mental illnesses in adolescence was 51.7%. Few teachers correctly answered about the life-time prevalences of major mental illness in general (21.9%), depression (37.8%) and schizophrenia (19.8%). Depression, schizophrenia and panic disorder in vignette were correctly recognized by 54.1, 35.3 and 78.0% of teachers, respectively. Correct recognition was significantly lower in male than in female teachers. Only a small proportion of teachers had confidence in helping depressed students (19.9%) and in teaching mental health knowledge to students (11.1%). CONCLUSIONS: MHL in Japanese high school teachers appears to be low. Education programs should be developed and implemented to improve teacher MHL with the aim of helping them to support students suffering from mental health problems.

Shorter sleep duration is associated with potential risks for overwork-related death among Japanese truck drivers: use of the Karoshi prodromes from worker's compensation cases.

PURPOSE: We aimed to cross-sectionally investigate how work and sleep conditions could be associated with excessive fatigue symptoms as an early sign of Karoshi (overwork-related cerebrovascular and cardiovascular diseases; CCVDs). METHODS: We distributed a questionnaire regarding work, sleep, and excessive fatigue symptoms to 5410 truck drivers, as the riskiest occupation for overwork-related CCVDs, and collected 1992 total samples (response rate: 36.8%). The research team collected 1564 investigation reports required for compensation for Karoshi. Of them, 190 reports listed the prodromes of Karoshi, which were used to develop the new excessive fatigue symptoms inventory. RESULTS: One-way analyses of variance showed that the excessive fatigue symptoms differed significantly by monthly overtime hours (p < 0.001), daily working time (p < 0.001), work schedule (p = 0.025), waiting time on-site (p = 0.049), number of night shifts (p = 0.011), and sleep duration on workdays (p < 0.001). Multivariate mixed-model regression analyses revealed shorter sleep duration as the most effective parameter for predicting excessive fatigue symptoms. Multiple logistic regression analysis confirmed that the occurrences of CCVDs were significantly higher in the middle [adjusted ORs = 3.56 (1.28-9.94)] and high-score groups [3.55 (1.24-10.21)] than in the low-score group. CONCLUSION: The findings suggested that shorter sleep duration was associated more closely with a marked increase in fatigue, as compared with the other work and sleep factors. Hence, ensuring sleep opportunities could be targeted for reducing the potential risks of Karoshi among truck drivers.

Does cognitive behavioral therapy for anxiety disorders assist the discontinuation of benzodiazepines among patients with anxiety disorders? A systematic review and meta-analysis.

Long-term use of benzodiazepines (BZD) is not recommended for the treatment of anxiety disorders. Cognitive behavioral therapy (CBT) is an effective treatment option for discontinuation of BZD in patients with anxiety disorders. This systematic review and meta-analysis sought to clarify whether CBT is effective for discontinuing BZD anxiolytics in patients with anxiety disorders. This study was preregistered with PROSPERO (registration number: CRD42019125263). A literature search of major electronic databases was conducted in December 2018. Three randomized controlled trials were included in this review, and meta-analyses were performed. The proportion of discontinuing BZD anxiolytics was significantly higher in the CBT plus gradual tapering group than in the gradual tapering alone group, both in the short term (3 months after allocation; number needed to treat: 3.2, 95% confidence interval [CI]: 2.1 to 7.1; risk ratio: 1.96, 95%CI: 1.29 to 2.98, P = 0.002, three studies) and long term (6 to 12 months after allocation; number needed to treat: 2.8, 95%CI: 1.9 to 5.3; risk ratio: 2.16, 95%CI: 1.41 to 3.32, P = 0.0004, three studies). CBT may be effective for discontinuing BZD anxiolytics, both in the short term and in the long term after the allocation. Further studies with larger sample sizes are necessary to draw definitive conclusions regarding the efficacy and safety of CBT for discontinuing BZD anxiolytics in patients with anxiety disorders.

Shared genetic etiology between anxiety disorders and psychiatric and related intermediate phenotypes.

BACKGROUND: Psychiatric disorders and related intermediate phenotypes are highly heritable and have a complex, overlapping polygenic architecture. A large-scale genome-wide association study (GWAS) of anxiety disorders identified genetic variants that are significant on a genome-wide. The current study investigated the genetic etiological overlaps between anxiety disorders and frequently cooccurring psychiatric disorders and intermediate phenotypes. METHODS: Using case-control and factor score models, we investigated the genetic correlations of anxiety disorders with eight psychiatric disorders and intermediate phenotypes [the volumes of seven subcortical brain regions, childhood cognition, general cognitive ability and personality traits (subjective well-being, loneliness, neuroticism and extraversion)] from large-scale GWASs (n = 7556-298 420) by linkage disequilibrium score regression. RESULTS: Among psychiatric disorders, the risk of anxiety disorders was positively genetically correlated with the risks of major depressive disorder (MDD) (rg ± standard error = 0.83 ± 0.16, p = 1.97 × 10-7), schizophrenia (SCZ) (0.28 ± 0.09, p = 1.10 × 10-3) and attention-deficit/hyperactivity disorder (ADHD) (0.34 ± 0.13, p = 8.40 × 10-3). Among intermediate phenotypes, significant genetic correlations existed between the risk of anxiety disorders and neuroticism (0.81 ± 0.17, p = 1.30 × 10-6), subjective well-being (-0.73 ± 0.18, p = 4.89 × 10-5), general cognitive ability (-0.23 ± 0.08, p = 4.70 × 10-3) and putamen volume (-0.50 ± 0.18, p = 5.00 × 10-3). No other significant genetic correlations between anxiety disorders and psychiatric or intermediate phenotypes were observed (p > 0.05). The case-control model yielded stronger genetic effect sizes than the factor score model. CONCLUSIONS: Our findings suggest that common genetic variants underlying the risk of anxiety disorders contribute to elevated risks of MDD, SCZ, ADHD and neuroticism and reduced quality of life, putamen volume and cognitive performance. We suggest that the comorbidity of anxiety disorders is partly explained by common genetic variants.

Use of social networking sites and desire for slimness among 10-year-old girls and boys: A population-based birth cohort study.

OBJECTIVE: Desire for slimness (DS) is a well-established risk factor for eating disorders among adolescents, particularly girls. It is known that exposure to traditional media such as television can increase DS. However, the association between DS and the use of new media, such as social networking sites (SNS), adjusting for relevant potential confounders, has not been examined to-date. In this study, we assessed the relationship between DS and SNS use among early adolescent girls and boys, adjusting for body mass index (BMI), time spent watching television, and Internet use. METHOD: DS, SNS use, and confounding variables were assessed using self-report questionnaires and face-to-face interviews from a cross-sectional population-based survey of 4,478 10-year-old Japanese adolescents (2,100 girls and 2,378 boys). RESULTS: After adjusting for confounding variables, SNS use was associated with increased risk of DS among girls (odds ratio [OR] = 1.93; 95% confidence interval [CI], 1.17-3.18, p = .010), but not among boys (OR = 1.07; 95% CI, 0.64-1.80, p = .786). DISCUSSION: Exposure to SNS was associated with an increased risk of DS among early adolescents, especially girls. Targeting SNS use in early adolescence seems a promising approach to prevention of DS and subsequent eating problems, particularly among girls.

A quasi-cluster randomized controlled trial of a classroom-based mental health literacy educational intervention to promote knowledge and help-seeking/helping behavior in adolescents.

INTRODUCTION: School-based education is a potentially effective approach for improving mental health literacy (MHL) in adolescents. This study evaluated the effects of the "Short MHL Program (SMHLP)", a brief (50 min), school teacher-led program, on MHL in adolescents in a quasi-cluster randomized controlled trial. METHODS: A total of 975 high school first graders (age 15-16) in Japan were allocated to classes such that gender and academic achievement ratios were almost equivalent at the time of admission to the high school. They were assigned at the class level to the SMHLP (n = 364 from 10 classes) or a control group (n = 611 from 17 classes). The program consisted of a 50-minute session and was delivered by a school teacher. The students completed a self-report questionnaire at 3 time points: pre-, (immediately) post- and 2-month follow-up. Outcomes included "Knowledge about mental health/illnesses", "Recognition of the necessity to seek help", "Intention to seek help", and "Intention of helping peers". Mixed effects modeling was employed for analyses. RESULTS: Scores of all outcomes were significantly improved in the intervention group compared to the control group post-intervention (p < .001). These improvements were maintained at 2-months follow-up for all outcomes (p < .001-.05). Questionnaire scores did not differ between groups at baseline. CONCLUSIONS: The effect of the SMHLP was confirmed in grade 10 students. Brief, yet effective programs can be a viable option to promote understanding of mental health problems and have the potential to be incorporated into regular school curriculum. ".

An epigenome-wide methylation study of healthy individuals with or without depressive symptoms.

Major depressive disorder is a common psychiatric disorder that is thought to be triggered by both genetic and environmental factors. Depressive symptoms are an important public health problem and contribute to vulnerability to major depression. Although a substantial number of genetic and epigenetic studies have been performed to date, the detailed etiology of depression remains unclear and there are no validated biomarkers. DNA methylation is one of the major epigenetic modifications that play diverse roles in the etiology of complex diseases. In this study, we performed an epigenome-wide association study (EWAS) of DNA methylation on subjects with (N = 20) or without (N = 27) depressive symptoms in order to examine whether different levels of DNA methylation were associated with depressive tendencies. Employing methylation-array technology, a total of 363,887 methylation sites across the genomes were investigated and several candidate CpG sites associated with depressive symptoms were identified, especially annotated to genes linked to a G-protein coupled receptor protein signaling pathway. These data provide a strong impetus for validation studies using a larger cohort and support the possibility that G-protein coupled receptor protein signaling pathways are involved in the pathogenesis of depression.

A variant at 9q34.11 is associated with HLA-DQB1*06:02 negative essential hypersomnia.

Essential hypersomnia (EHS) is a lifelong disorder characterized by excessive daytime sleepiness without cataplexy. EHS is associated with human leukocyte antigen (HLA)-DQB1*06:02, similar to narcolepsy with cataplexy (narcolepsy). Previous studies suggest that DQB1*06:02-positive and -negative EHS are different in terms of their clinical features and follow different pathological pathways. DQB1*06:02-positive EHS and narcolepsy share the same susceptibility genes. In the present study, we report a genome-wide association study with replication for DQB1*06:02-negative EHS (408 patients and 2247 healthy controls, all Japanese). One single-nucleotide polymorphism, rs10988217, which is located 15-kb upstream of carnitine O-acetyltransferase (CRAT), was significantly associated with DQB1*06:02-negative EHS (P = 7.5 × 10-9, odds ratio = 2.63). The risk allele of the disease-associated SNP was correlated with higher expression levels of CRAT in various tissues and cell types, including brain tissue. In addition, the risk allele was associated with levels of succinylcarnitine (P = 1.4 × 10-18) in human blood. The leading SNP in this region was the same in associations with both DQB1*06:02-negative EHS and succinylcarnitine levels. The results suggest that DQB1*06:02-negative EHS may be associated with an underlying dysfunction in energy metabolic pathways.

Mutations of the glycine cleavage system genes possibly affect the negative symptoms of schizophrenia through metabolomic profile changes.

AIM: Hypofunction of N-methyl-D-aspartate receptors (NMDAR) may contribute to the pathophysiology of schizophrenia (SCZ). Recently, the glycine cleavage system (GCS) was shown to affect NMDAR function in the brain. GCS functional defects cause nonketotic hyperglycinemia, the atypical phenotype of which presents psychiatric symptoms similar to SCZ. Here, we examined the involvement of GCS in SCZ. METHODS: First, to identify the rare variants and the exonic deletions, we resequenced all the coding exons and the splice sites of four GCS genes (GLDC, AMT, GCSH, and DLD) in 474 patients with SCZ and 475 controls and performed multiplex ligation-dependent probe amplification analysis in SCZ. Next, we performed metabolome analysis using plasma of patients harboring GCS variants (n = 5) and controls (n = 5) by capillary electrophoresis time-of-flight mass spectrometry. The correlation between plasma metabolites and Positive and Negative Syndrome Scale score was further examined. RESULTS: Possibly damaging variants were observed in SCZ: A203V, S801N in GLDC, near the atypical nonketotic hyperglycinemia causative mutations (A202V, A802V); G825D in GLDC, a potential neural tube defect causative mutation; and R253X in AMT. Marked elevation of plasma 5-oxoproline (pyroglutamic acid), aspartate, and glutamate, which might affect NMDAR function, was observed in patients harboring GCS variants. The aspartate level inversely correlated with negative symptoms (r = -0.942, P = 0.0166). CONCLUSION: These results suggest that GCS rare variants possibly contribute to the pathophysiology of SCZ by affecting the negative symptoms through elevation of aspartate.

DNA methylation analyses of the candidate genes identified by a methylome-wide association study revealed common epigenetic alterations in schizophrenia and bipolar disorder.

AIM: Schizophrenia (SZ) and bipolar disorder (BD) have been known to share genetic and environmental risk factors, and complex gene-environmental interactions may contribute to their pathophysiology. In contrast to high genetic overlap between SZ and BD, as revealed by genome-wide association studies, the extent of epigenetic overlap remains largely unknown. In the present study, we explored whether SZ and BD share epigenetic risk factors in the same manner as they share genetic components. METHODS: We performed DNA methylation analyses of the CpG sites in the top five candidate regions (FAM63B, ARHGAP26, CTAGE11P, TBC1D22A, and intergenic region [IR] on chromosome 16) reported in a previous methylome-wide association study (MWAS) of SZ, using whole blood samples from subjects with BD and controls. RESULTS: Among the five candidate regions, the CpG sites in FAM63B and IR on chromosome 16 were significantly hypomethylated in the samples from subjects with BD as well as those from subjects with SZ. On the other hand, the CpG sites in TBC1D22A were hypermethylated in the samples from subjects with BD, in contrast to hypomethylation in the samples from subjects with SZ. CONCLUSION: Hypomethylation of FAM63B and IR on chromosome 16 could be common epigenetic risk factors for SZ and BD. Further comprehensive epigenetic studies for BD, such as MWAS, will uncover the extent of similarity and uniqueness of epigenetic alterations.

Disciplinary slapping is associated with bullying involvement regardless of warm parenting in early adolescence.

INTRODUCTION: Bullying among adolescents can cause depression and suicidality. Identifying the risk factors for bullying in early adolescence, when its prevalence tends to increase, would assist in its prevention. Although certain parenting styles are known to be associated with bullying, the association of slapping as a parental disciplinary practice with early adolescent bullying is not sufficiently understood. Furthermore, little is known about how warm parenting modifies this association although slapping and warm parenting are not mutually exclusive. The aim of this study was to investigate the association of slapping with the experience of early adolescent bullying--categorized in terms of victims, bullies, and bully-victims--while considering how warm parenting modifies this association. METHODS: This study used data from the Tokyo Early Adolescence Survey, a cross-sectional survey of 4478 children aged 10 from the general population. Data were collected from both children and their primary parent using self-administered questionnaires and face-to-face interviews. Responses from 4326 participants with no missing data were usable for the current analysis (mean age,  10.2 ±â€¯0.3 years; 53 % boys). RESULTS: Frequent and occasional slapping was associated with increased odds of youth being identified as bullies or bully-victims, even after adjusting for warm parenting. The likelihood of being victims, bullies or bully-victims increased as the frequency of slapping increased. CONCLUSION: Disciplinary slapping was associated with increased odds of bullying in early adolescence, regardless of whether warm parenting was present or not.

Appetite loss as a potential predictor of suicidal ideation and self-harm in adolescents: A school-based study.

Suicide is a leading cause of death in adolescents, but detection of its risk is often challenging. Many mental illnesses share the common symptom of appetite loss and it is also known that people who suffer from these illnesses are at greater risk of suicide. However, the relationship between appetite loss and suicide risk has yet to be examined. For adolescents in particular, questions about appetite loss may be easier to answer than sensitive questions regarding mental health. The present study aims to investigate the association of appetite loss with suicidal ideation and self-harm in adolescents. Rates of adolescents with suicidal ideation or self-harm associated with appetite-loss were examined in 18,250 Japanese junior and senior high school students (aged 12-18) using a self-report questionnaire. Insomnia, a physical symptom which has previously been associated with suicide risk, was also controlled for in the analysis. Results showed that rates of adolescents with suicidal ideation or self-harm significantly increased according to the degree of self-reported appetite loss. Similar results were observed for insomnia. Odds ratios (ORs) for suicidal ideation and self-harm were 5.5 and 4.1 for adolescents with appetite loss compared to those without it, and the ORs were 5.5 and 3.5 for those with insomnia compared to those without it, respectively, adjusting for sex and age (p < 0.001). ORs remained statistically significant after adjusting for depression/anxiety (General Health Questionnaire-12 score). In conclusion, self-reported appetite loss was highly associated with suicidal ideation and self-harm in adolescents; adolescents reporting physical symptoms such as loss of appetite or insomnia should be given careful attention.

Identification of candidate genes involved in the etiology of sporadic Tourette syndrome by exome sequencing.

Tourette Syndrome (TS) is a neurodevelopmental disorder characterized by chronic motor and vocal tics. Although there is a large genetic contribution, the genetic architecture of TS remains unclear. Exome sequencing has successfully revealed the contribution of de novo mutations in sporadic cases with neuropsychiatric disorders such as autism and schizophrenia. Here, using exome sequencing, we investigated de novo mutations in individuals with sporadic TS to identify novel risk loci and elucidate the genetic background of TS. Exome analysis was conducted for sporadic TS cases: nine trio families and one quartet family with concordant twins were investigated. Missense mutations were evaluated using functional prediction algorithms, and their population frequencies were calculated based on three public databases. Gene expression patterns in the brain were analyzed using the BrainSpan Developmental Transcriptome. Thirty de novo mutations, including four synonymous and four missense mutations, were identified. Among the missense mutations, one in the rapamycin-insensitive companion of mammalian target of rapamycin (RICTOR)-coding gene (rs140964083: G > A, found in one proband) was predicted to be hazardous. In the three public databases analyzed, variants in the same SNP locus were absent, and variants in the same gene were either absent or present at an extremely low frequency (3/5,008), indicating the rarity of hazardous RICTOR mutations in the general population. The de novo variant of RICTOR may be implicated in the development of sporadic TS, and RICTOR is a novel candidate factor for TS etiology.

Evaluation of polygenic risks for narcolepsy and essential hypersomnia.

In humans, narcolepsy is a sleep disorder that is characterized by sleepiness, cataplexy and rapid eye movement (REM) sleep abnormalities. Essential hypersomnia (EHS) is another type of sleep disorder that is characterized by excessive daytime sleepiness without cataplexy. A human leukocyte antigen (HLA) class II allele, HLA-DQB1*06:02, is a major genetic factor for narcolepsy. Almost all narcoleptic patients are carriers of this HLA allele, while 30-50% of EHS patients and 12% of all healthy individuals in Japan carry this allele. The pathogenesis of narcolepsy and EHS is thought to be partially shared. To evaluate the contribution of common single-nucleotide polymorphisms (SNPs) to narcolepsy onset and to assess the common genetic background of narcolepsy and EHS, we conducted a polygenic analysis that included 393 narcoleptic patients, 38 EHS patients with HLA-DQB1*06:02, 119 EHS patients without HLA-DQB1*06:02 and 1582 healthy individuals. We also included 376 individuals with panic disorder and 213 individuals with autism to confirm whether the results were biased. Polygenic risks in narcolepsy were estimated to explain 58.1% (PHLA-DQB1*06:02=2.30 × 10-48, Pwhole genome without HLA-DQB1*06:02=6.73 × 10-2) including HLA-DQB1*06:02 effects and 1.3% (Pwhole genome without HLA-DQB1*06:02=2.43 × 10-2) excluding HLA-DQB1*06:02 effects. The results also indicated that small-effect SNPs contributed to the development of narcolepsy. Reported susceptibility SNPs for narcolepsy in the Japanese population, CPT1B (carnitine palmitoyltransferase 1B), TRA@ (T-cell receptor alpha) and P2RY11 (purinergic receptor P2Y, G-protein coupled, 11), were found to explain 0.8% of narcolepsy onset (Pwhole genome without HLA-DQB1*06:02=9.74 × 10-2). EHS patients with HLA-DQB1*06:02 were estimated to have higher shared genetic background to narcoleptic patients than EHS patients without HLA-DQB1*06:02 even when the effects of HLA-DQB1*06:02 were excluded (EHS with HLA-DQB1*06:02: 40.4%, PHLA-DQB1*06:02=7.02 × 10-14, Pwhole genome without HLA-DQB1*06:02=1.34 × 10-1, EHS without HLA-DQB1*06:02: 0.4%, Pwhole genome without HLA-DQB1*06:02=3.06 × 10-1). Meanwhile, the polygenic risks for narcolepsy could not explain the onset of panic disorder and autism, suggesting that our results were reasonable.