Machine learning algorithm-based estimation model for the severity of depression assessed using Montgomery-Asberg depression rating scale.

AIM: Depressive disorder is often evaluated using established rating scales. However, consistent data collection with these scales requires trained professionals. In the present study, the "rater & estimation-system" reliability was assessed between consensus evaluation by trained psychiatrists and the estimation by 2 models of the AI-MADRS (Montgomery-Asberg Depression Rating Scale) estimation system, a machine learning algorithm-based model developed to assess the severity of depression. METHODS: During interviews with trained psychiatrists and the AI-MADRS estimation system, patients responded orally to machine-generated voice prompts from the AI-MADRS structured interview questions. The severity scores estimated from two models of the AI-MADRS estimation system, the max estimation model and the average estimation model, were compared with those by trained psychiatrists. RESULTS: A total of 51 evaluation interviews conducted on 30 patients were analyzed. Pearson's correlation coefficient with the scores evaluated by trained psychiatrists was 0.76 (95% confidence interval 0.62-0.86) for the max estimation model, and 0.86 (0.76-0.92) for the average estimation model. The ANOVA ICC rater & estimation-system reliability with the evaluation scores by trained psychiatrists was 0.51 (-0.09 to 0.79) for the max estimation model, and 0.75 (0.55-0.86) for the average estimation model. CONCLUSION: The average estimation model of AI-MADRS demonstrated substantially acceptable rater & estimation-system reliability with trained psychiatrists. Accumulating a broader training dataset and the refinement of AI-MADRS interviews are expected to improve the performance of AI-MADRS. Our findings suggest that AI technologies can significantly modernize and potentially revolutionize the realm of depression assessments.

Molecular diagnosis of 405 individuals with autism spectrum disorder.

Autism spectrum disorder (ASD) is caused by combined genetic and environmental factors. Genetic heritability in ASD is estimated as 60-90%, and genetic investigations have revealed many monogenic factors. We analyzed 405 patients with ASD using family-based exome sequencing to detect disease-causing single-nucleotide variants (SNVs), small insertions and deletions (indels), and copy number variations (CNVs) for molecular diagnoses. All candidate variants were validated by Sanger sequencing or quantitative polymerase chain reaction and were evaluated using the American College of Medical Genetics and Genomics/Association for Molecular Pathology guidelines for molecular diagnosis. We identified 55 disease-causing SNVs/indels in 53 affected individuals and 13 disease-causing CNVs in 13 affected individuals, achieving a molecular diagnosis in 66 of 405 affected individuals (16.3%). Among the 55 disease-causing SNVs/indels, 51 occurred de novo, 2 were compound heterozygous (in one patient), and 2 were X-linked hemizygous variants inherited from unaffected mothers. The molecular diagnosis rate in females was significantly higher than that in males. We analyzed affected sibling cases of 24 quads and 2 quintets, but only one pair of siblings shared an identical pathogenic variant. Notably, there was a higher molecular diagnostic rate in simplex cases than in multiplex families. Our simulation indicated that the diagnostic yield is increasing by 0.63% (range 0-2.5%) per year. Based on our simple simulation, diagnostic yield is improving over time. Thus, periodical reevaluation of ES data should be strongly encouraged in undiagnosed ASD patients.

Investigation of OLIG2 as a candidate gene for schizophrenia and autism spectrum disorder.

A number of genomic mutations that are thought to be strongly involved in the development of schizophrenia (SCZ) and autism spectrum disorder (ASD) have been identified. Abnormalities involving oligodendrocytes have been reported in SCZ, and as a related gene, oligodendrocyte lineage transcription factor 2 (OLIG2) has been reported to be strongly associated with SCZ. In this study, based on the common disease-rare variant hypothesis, target sequencing of candidate genes was performed to identify rare mutations with a high effect size and the possibility that the identified mutations may increase the risks of SCZ and ASD in the Japanese population. In this study, the exon region of OLIG2 was targeted; 370 patients with SCZ and 192 with ASD were subjected to next-generation sequencing. As a result, one rare missense mutation (A33T) was detected. We used the Sanger method to validate this missense mutation with a low frequency (<1%), and then carried out a genetic association analysis involving 3299 unrelated individuals (1447 with SCZ, 380 with ASD, and 1472 healthy controls) to clarify whether A33T was associated with SCZ or ASD. A33T was not found in either case group, and in only one control. We did not find evidence that p.A33T is involved in the onset of ASD or SCZ; however, associations with this variant need to be evaluated in larger samples to confirm our results.

Exome sequencing analysis of Japanese autism spectrum disorder case-control sample supports an increased burden of synaptic function-related genes.

Autism spectrum disorder (ASD) is a highly heritable, complex disorder in which rare variants contribute significantly to disease risk. Although many genes have been associated with ASD, there have been few genetic studies of ASD in the Japanese population. In whole exomes from a Japanese ASD sample of 309 cases and 299 controls, rare variants were associated with ASD within specific neurodevelopmental gene sets, including highly constrained genes, fragile X mental retardation protein target genes, and genes involved in synaptic function, with the strongest enrichment in trans-synaptic signaling (p = 4.4 × 10-4, Q-value = 0.06). In particular, we strengthen the evidence regarding the role of ABCA13, a synaptic function-related gene, in Japanese ASD. The overall results of this case-control exome study showed that rare variants related to synaptic function are associated with ASD susceptibility in the Japanese population.

Cross-Disorder Analysis of Genic and Regulatory Copy Number Variations in Bipolar Disorder, Schizophrenia, and Autism Spectrum Disorder.

BACKGROUND: We aimed to determine the similarities and differences in the roles of genic and regulatory copy number variations (CNVs) in bipolar disorder (BD), schizophrenia (SCZ), and autism spectrum disorder (ASD). METHODS: Based on high-resolution CNV data from 8708 Japanese samples, we performed to our knowledge the largest cross-disorder analysis of genic and regulatory CNVs in BD, SCZ, and ASD. RESULTS: In genic CNVs, we found an increased burden of smaller (<100 kb) exonic deletions in BD, which contrasted with the highest burden of larger (>500 kb) exonic CNVs in SCZ/ASD. Pathogenic CNVs linked to neurodevelopmental disorders were significantly associated with the risk for each disorder, but BD and SCZ/ASD differed in terms of the effect size (smaller in BD) and subtype distribution of CNVs linked to neurodevelopmental disorders. We identified 3 synaptic genes (DLG2, PCDH15, and ASTN2) as risk factors for BD. Whereas gene set analysis showed that BD-associated pathways were restricted to chromatin biology, SCZ and ASD involved more extensive and similar pathways. Nevertheless, a correlation analysis of gene set results indicated weak but significant pathway similarities between BD and SCZ or ASD (r = 0.25-0.31). In SCZ and ASD, but not BD, CNVs were significantly enriched in enhancers and promoters in brain tissue. CONCLUSIONS: BD and SCZ/ASD differ in terms of CNV burden, characteristics of CNVs linked to neurodevelopmental disorders, and regulatory CNVs. On the other hand, they have shared molecular mechanisms, including chromatin biology. The BD risk genes identified here could provide insight into the pathogenesis of BD.

Exome sequencing of Japanese schizophrenia multiplex families supports the involvement of calcium ion channels.

BACKGROUND: Most sequencing studies of schizophrenia (SCZ) have focused on de novo genetic variants due to interpretability. However, investigating shared rare variants among patients in the same multiplex family is also important. Relatively large-scale analyses of SCZ multiplex families have been done in Caucasian populations, but whether detected variants are also pathogenic in the Japanese population is unclear because of ethnic differences in rare variants. MATERIALS AND METHODS: We performed whole-exome sequencing (WES) of 14 Japanese SCZ multiplex families. After quality control and filtering, we identified rare variants shared among affected persons within the same family. A gene ontology (GO) analysis was performed to identify gene categories possibly affected by these candidate variants. RESULTS: We found 530 variants in 486 genes as potential candidate variants from the 14 SCZ multiplex families examined. The GO analysis demonstrated significant enrichment in calcium channel activity. CONCLUSION: This study provides supporting evidence that calcium ion channel activity is involved in SCZ. WES of multiplex families is a potential means of identifying disease-associated rare variants for SCZ.

Identification of ultra-rare disruptive variants in voltage-gated calcium channel-encoding genes in Japanese samples of schizophrenia and autism spectrum disorder.

Several large-scale whole-exome sequencing studies in patients with schizophrenia (SCZ) and autism spectrum disorder (ASD) have identified rare variants with modest or strong effect size as genetic risk factors. Dysregulation of cellular calcium homeostasis might be involved in SCZ/ASD pathogenesis, and genes encoding L-type voltage-gated calcium channel (VGCC) subunits Cav1.1 (CACNA1S), Cav1.2 (CACNA1C), Cav1.3 (CACNA1D), and T-type VGCC subunit Cav3.3 (CACNA1I) recently were identified as risk loci for psychiatric disorders. We performed a screening study, using the Ion Torrent Personal Genome Machine (PGM), of exon regions of these four candidate genes (CACNA1C, CACNA1D, CACNA1S, CACNA1I) in 370 Japanese patients with SCZ and 192 with ASD. Variant filtering was applied to identify biologically relevant mutations that were not registered in the dbSNP database or that have a minor allele frequency of less than 1% in East-Asian samples from databases; and are potentially disruptive, including nonsense, frameshift, canonical splicing site single nucleotide variants (SNVs), and non-synonymous SNVs predicted as damaging by five different in silico analyses. Each of these filtered mutations were confirmed by Sanger sequencing. If parental samples were available, segregation analysis was employed for measuring the inheritance pattern. Using our filter, we discovered one nonsense SNV (p.C1451* in CACNA1D), one de novo SNV (p.A36V in CACNA1C), one rare short deletion (p.E1675del in CACNA1D), and 14 NSstrict SNVs (non-synonymous SNV predicted as damaging by all of five in silico analyses). Neither p.A36V in CACNA1C nor p.C1451* in CACNA1D were found in 1871 SCZ cases, 380 ASD cases, or 1916 healthy controls in the independent sample set, suggesting that these SNVs might be ultra-rare SNVs in the Japanese population. The neuronal splicing isoform of Cav1.2 with the p.A36V mutation, discovered in the present study, showed reduced Ca2+-dependent inhibition, resulting in excessive Ca2+ entry through the mutant channel. These results suggested that this de novo SNV in CACNA1C might predispose to SCZ by affecting Ca2+ homeostasis. Thus, our analysis successfully identified several ultra-rare and potentially disruptive gene variants, lending partial support to the hypothesis that VGCC-encoding genes may contribute to the risk of SCZ/ASD.

Autistic traits as predictors of persistent depression.

Persistent depression has been suggested to be associated with autistic traits in people of working age. This study aimed to clarify which autistic characteristics at the initial visit were associated with persistent depression at the 12 week follow-up in a primary care setting. Newly depressed outpatients aged 24-59 years with no history of autism were asked to complete the 50-item autism spectrum quotient (AQ) and the Beck depression inventory (BDI) at baseline and 12 week follow-up (N = 123, males: 48%, age: 37.7 ± 9.15 years). Nearly 40% of participants had an AQ score ≥ 26. Significant differences were observed between the group with remitted depression (N = 43) and those with persistent depression (N = 80) in educational years and AQ "attention switching" and "attention to detail" subscale scores. In addition, a statistically significant decrease in the total AQ and the "communication" and "imagination" scores were observed in the remitted group, while no such change was observed in the group with persistent depression. It remains unclear whether the self-perceived severity of communication and imagination traits in persistent depression was due to the state of persistent depression or a kind of premorbid autistic trait. The results suggest that high levels of autistic traits are frequently present in adults with depression. High "attention switching" and "attention to detail" scores in AQ screening at the first visit might predict the persistence of depressive symptoms after 12 weeks in adults with depression, while total AQ scores, especially for "communication" and "imagination" items, might be state-dependent.

Psychosocial characteristics of alcoholic and non-alcoholic liver disease recipient candidates in liver transplantation: a prospective observational study.

BACKGROUND: There are long-standing controversies about the transplant indications for alcoholic liver disease (ALD), because of the recognition that ALD is fundamentally self-inflicted. However, it is unclear whether psychosocial characteristics of ALD are different from that of non-alcoholic liver disease (NALD) in the selection of liver transplantation (LT) recipients. We aimed to clarify the psychosocial characteristics of ALD recipients (ALD-R)/ALD recipient candidates (ALD-RC) and NALD recipients (NALD-R)/ NALD recipient candidates (NALD-RC). METHODS: From 2011 to 2019, 75 patients were enrolled in this prospective observational study (ALD-RC, n = 19; NALD-RC, n = 56), LT were carried out as follow; ALD-R, n = 6; NALD-R, n = 52. We evaluated psychosocial characteristics in the preoperative period and 3, 12 months after LT (ALD-R, n = 3/3; NALD-R, n = 28/25). The following scales were used to evaluate psychosocial characteristics: Visual Analogue Scale, Alcohol Use Disorders Identification Test, Hospital Anxiety and Depression Scale, Beck Depression Inventory, Brief Evaluation of Medication Influences and Beliefs, Social Support Questionnaire (SSQ), Temperament and Character Inventory, Parental Bonding Instrument (PBI), the Short Form Health Survey (SF-36). RESULTS: When evaluating on the basis of abstinence rule, a comparison of ALD-RC and NALD-RC in the preoperative period identified similar patterns of psychosocial characteristics, except that the NALD-RC scored higher on the PBI item "overprotection from mother" (P < 0.05). The only significant difference between ALD-R and NALD-R after liver transplantation was in SSQ scores at 3 months. CONCLUSION: The psychosocial characteristics of ALD-RC and NALD-RC may be similar when evaluated on the basis of Japan's abstinence rule. This result also imply that the psychosocial characteristics of ALD-RC may differ from the previously reported psychosocial characteristics of alcohol dependent patients. These findings have the potential to provide helpful information for the evaluation of ALD-RC.

Establishment of in-hospital clinical network for patients with neurofibromatosis type 1 in Nagoya University Hospital.

Neurofibromatosis type 1 (NF1) is a genetic multisystem disorder. Clinicians must be aware of the diverse clinical features of this disorder in order to provide optimal care for it. We have set up an NF1 in-hospital medical care network of specialists regardless of patient age, launching a multidisciplinary approach to the disease for the first time in Japan. From January 2014 to December 2020, 246 patients were enrolled in the NF1 patient list and medical records. Mean age was 26.0 years ranging from 3 months to 80 years. The number of patients was higher as age at first visit was lower. There were 107 males (41%) and 139 females. After 2011, the number of patients has increased since the year when the medical care network was started. Regarding orthopedic signs, scoliosis was present in 60 cases (26%), and bone abnormalities in the upper arm, forearm, and tibia in 8 cases (3.5%). Neurofibromas other than cutaneous neurofibromas were present in 90 cases (39%), and MPNST in 17 cases (7.4%). We launched a multidisciplinary NF1 clinic system for the first time in Japan. For patients with NF1, which is a hereditary and systemic disease associated with a high incidence of malignant tumors, it will be of great benefit when the number of such clinics in Japan and the rest of Asia is increased.

Peripheral biomarkers of attention-deficit hyperactivity disorder: Current status and future perspective.

Attention-deficit hyperactivity disorder (ADHD) is one of the most common neurodevelopmental disorders, characterized by a persistent pattern of inattention, hyperactivity, and impulsivity. Since the diagnosis of ADHD is defined by operational diagnostic criteria consisting of several clinical symptoms, a number of heterogeneous mechanisms have been considered to be implicated in its pathophysiology. Although no clinically reliable biomarkers are available for the diagnosis of ADHD, several plausible candidate biomarkers have been proposed based on recent advances in biochemistry and molecular biology. This review article summarizes potential peripheral biomarkers associated with ADHD, mainly from recently published case-control studies. These include 1) biochemical markers: neurotransmitters and their receptors, neurotrophic factors, serum electrolytes, and inflammation markers; 2) genetic and epigenetic markers: microRNA, mRNA expression, and peripheral DNA methylation; 3) physiological markers: eye movement and electroencephalography. It also discusses the limitations and future directions of these potential biomarkers for application in clinical practice.

Depressive mood changes are associated with self-perceptions of ADHD characteristics in adults.

Subjective attention deficit/hyperactivity disorder (ADHD) symptoms seen in adult depressive patients have often become a pathophysiological topic in recent years. Screening questionnaires are widely used for detecting ADHD; however, the risk of misdiagnosis exists. The present study examined whether self-perceptions of ADHD-related characteristics were consistent regardless of changes in the severity of depressive symptoms. Between April to October 2018, newly diagnosed depressed outpatients aged 24-59 years with good social functioning and without a history of ADHD were asked to fill out the Adult ADHD Self-Report Scale version 1.1 (ASRS) and the Beck Depression Inventory (BDI) at baseline (n = 726) and 12-week follow-up (n = 202). A statistically significant correlation was found between a change in BDI and ASRS scores (score at baseline minus score at the endpoint; r = .57). In addition, the higher the rate of improvement in BDI, the lower the frequency of positive screening for ADHD by ASRS. This study showed that subjective ADHD symptoms were correlated with depressive states. Diagnostic evaluation of comorbid ADHD using self-report scales in a primary care setting should be made with caution.

Rare single-nucleotide DAB1 variants and their contribution to Schizophrenia and autism spectrum disorder susceptibility.

Disabled 1 (DAB1) is an intracellular adaptor protein in the Reelin signaling pathway and plays an essential role in correct neuronal migration and layer formation in the developing brain. DAB1 has been repeatedly reported to be associated with neurodevelopmental disorders including schizophrenia (SCZ) and autism spectrum disorders (ASD) in genetic, animal, and postmortem studies. Recently, increasing attention has been given to rare single-nucleotide variants (SNVs) found by deep sequencing of candidate genes. In this study, we performed exon-targeted resequencing of DAB1 in 370 SCZ and 192 ASD patients using next-generation sequencing technology to identify rare SNVs with a minor allele frequency <1%. We detected two rare missense mutations (G382C, V129I) and then performed a genetic association study in a sample comprising 1763 SCZ, 380 ASD, and 2190 healthy control subjects. Although no statistically significant association with the detected mutations was observed for either SCZ or ASD, G382C was found only in the case group, and in silico analyses and in vitro functional assays suggested that G382C alters the function of the DAB1 protein. The rare variants of DAB1 found in the present study should be studied further to elucidate their potential functional relevance to the pathophysiology of SCZ and ASD.

Rare genetic variants in the gene encoding histone lysine demethylase 4C (KDM4C) and their contributions to susceptibility to schizophrenia and autism spectrum disorder.

Dysregulation of epigenetic processes involving histone methylation induces neurodevelopmental impairments and has been implicated in schizophrenia (SCZ) and autism spectrum disorder (ASD). Variants in the gene encoding lysine demethylase 4C (KDM4C) have been suggested to confer a risk for such disorders. However, rare genetic variants in KDM4C have not been fully evaluated, and the functional impact of the variants has not been studied using patient-derived cells. In this study, we conducted copy number variant (CNV) analysis in a Japanese sample set (2605 SCZ and 1141 ASD cases, and 2310 controls). We found evidence for significant associations between CNVs in KDM4C and SCZ (p = 0.003) and ASD (p = 0.04). We also observed a significant association between deletions in KDM4C and SCZ (corrected p = 0.04). Next, to explore the contribution of single nucleotide variants in KDM4C, we sequenced the coding exons in a second sample set (370 SCZ and 192 ASD cases) and detected 18 rare missense variants, including p.D160N within the JmjC domain of KDM4C. We, then, performed association analysis for p.D160N in a third sample set (1751 SCZ and 377 ASD cases, and 2276 controls), but did not find a statistical association with these disorders. Immunoblotting analysis using lymphoblastoid cell lines from a case with KDM4C deletion revealed reduced KDM4C protein expression and altered histone methylation patterns. In conclusion, this study strengthens the evidence for associations between KDM4C CNVs and these two disorders and for their potential functional effect on histone methylation patterns.