Extremely Low Frequency, Extremely Low Magnetic Environment for depression: An open-label trial.

Mitochondrial dysfunction has been suggested to play a role in depression pathogenesis. This clinical trial (jRCTs042220011) was conducted to evaluate whether depression symptoms could be alleviated by an Extremely Low Frequency, Extremely Low Magnetic Environment (ELF-ELME), which has been found in basic research studies to enhance mitochondrial membrane potential. Participants were exposed to the ELF-ELME via a head-mounted magnetic field device (10 µTesla, 4 ms, 1-8 Hz/8 s) worn for 2 h per day for 8 consecutive weeks. Four male patients with treatment-resistant depression were enrolled. Significant reductions from baseline in the average total Montgomery-Åsberg Depression Rating Scale (MADRS) score were observed at 4, 6, and 8 weeks. ELF-ELME appears to ameliorate depressive symptoms in patients with major depressive disorder safely and effectively, suggesting that it could be used as an alternative treatment for depressive patients who do not prefer to take antidepressants and in combination with antidepressant therapy for patients who only partially respond to pharmacotherapy.

Phenotypes for general behavior, activity, and body temperature in 3q29 deletion model mice.

Whole genome analysis has identified rare copy number variations (CNV) that are strongly involved in the pathogenesis of psychiatric disorders, and 3q29 deletion has been found to have the largest effect size. The 3q29 deletion mice model (3q29-del mice) has been established as a good pathological model for schizophrenia based on phenotypic analysis; however, circadian rhythm and sleep, which are also closely related to neuropsychiatric disorders, have not been investigated. In this study, our aims were to reevaluate the pathogenesis of 3q29-del by recreating model mice and analyzing their behavior and to identify novel new insights into the temporal activity and temperature fluctuations of the mouse model using a recently developed small implantable accelerometer chip, Nano-tag. We generated 3q29-del mice using genome editing technology and reevaluated common behavioral phenotypes. We next implanted Nano-tag in the abdominal cavity of mice for continuous measurements of long-time activity and body temperature. Our model mice exhibited weight loss similar to that of other mice reported previously. A general behavioral battery test in the model mice revealed phenotypes similar to those observed in mouse models of schizophrenia, including increased rearing frequency. Intraperitoneal implantation of Nano-tag, a miniature acceleration sensor, resulted in hypersensitive and rapid increases in the activity and body temperature of 3q29-del mice upon switching to lights-off condition. Similar to the 3q29-del mice reported previously, these mice are a promising model animals for schizophrenia. Successive quantitative analysis may provide results that could help in treating sleep disorders closely associated with neuropsychiatric disorders.

Indoleamine 2,3-dioxygenase 2 deficiency associates with autism-like behavior via dopaminergic neuronal dysfunction.

Indoleamine 2,3-dioxygenase 2 (IDO2) is an enzyme of the tryptophan-kynurenine pathway that is constitutively expressed in the brain. To provide insight into the physiological role of IDO2 in the brain, behavioral and neurochemical analyses in IDO2 knockout (KO) mice were performed. IDO2 KO mice showed stereotyped behavior, restricted interest and social deficits, traits that are associated with behavioral endophenotypes of autism spectrum disorder (ASD). IDO2 was colocalized immunohistochemically with tyrosine-hydroxylase-positive cells in dopaminergic neurons. In the striatum and amygdala of IDO2 KO mice, decreased dopamine turnover was associated with increased α-synuclein level. Correspondingly, levels of downstream dopamine D1 receptor signaling molecules such as brain-derived neurotrophic factor and c-Fos positive proteins were decreased. Furthermore, decreased abundance of ramified-type microglia resulted in increased dendritic spine density in the striatum of IDO2 KO mice. Both chemogenetic activation of dopaminergic neurons and treatment with methylphenidate, a dopamine reuptake inhibitor, ameliorated the ASD-like behavior of IDO2 KO mice. Sequencing analysis of exon regions in IDO2 from 309 ASD samples identified a rare canonical splice site variant in one ASD case. These results suggest that the IDO2 gene is, at least in part, a factor closely related to the development of psychiatric disorders.

Association between copy number variations in parkin (PRKN) and schizophrenia and autism spectrum disorder: A case-control study.

AIM: The present study aimed to examine the association between copy number variations (CNVs) in parkin (PRKN) and schizophrenia (SCZ) and autism spectrum disorder (ASD) in a large case-control sample. METHOD: Array comparative genomic hybridization was performed on 3111 cases with SCZ, 1236 cases with ASD, and 2713 controls. We systematically prioritized likely pathogenic CNVs (LP-CNVs) in PRKN and examined their association with SCZ and ASD. RESULTS: In total, 3014 SCZ cases (96.9%), 1205 ASD cases (97.5%), and 2671 controls (98.5%) passed quality control. We found that monoallelic carriers of LP-CNVs in PRKN were common (70/6890, 1.02%) and were not at higher risk of SCZ (p = 0.29) or ASD (p = 0.72). We observed that the distribution pattern of LP-CNVs in the Japanese population was consistent with those in other populations. We also identified a patient diagnosed with SCZ and early-onset Parkinson's disease carrying biallelic pathogenic CNVs in PRKN. The absence of Parkinson's symptoms in 10 other monoallelic carriers of the same pathogenic CNV further reflects the lack of effect of monoallelic pathogenic variants in PRKN in the absence of a second hit. CONCLUSION: The present findings suggest that monoallelic CNVs in PRKN do not confer a significant risk for SCZ or ASD. However, further studies to investigate the association between biallelic CNVs in PRKN and SCZ and ASD are warranted.

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.

Apoptosis inhibitor of macrophage (AIM)/CD5L is involved in the pathogenesis of COPD.

BACKGROUND: Alveolar macrophages (AMs) and AM-produced matrix metalloprotease (MMP)-12 are known to play critical roles in the pathogenesis of chronic obstructive pulmonary disease (COPD). The apoptosis inhibitor of the macrophages (AIM)/CD5 molecule-like (CD5L) is a multifunctional protein secreted by the macrophages that mainly exists in the blood in a combined form with the immunoglobulin (Ig)M pentamer. Although AIM has both facilitative and suppressive roles in various diseases, its role in COPD remains unclear. METHODS: We investigated the role of AIM in COPD pathogenesis using porcine pancreas elastase (PPE)-induced and cigarette smoke-induced emphysema mouse models and an in vitro model using AMs. We also analyzed the differences in the blood AIM/IgM ratio among nonsmokers, healthy smokers, and patients with COPD and investigated the association between the blood AIM/IgM ratio and COPD exacerbations and mortality in patients with COPD. RESULTS: Emphysema formation, inflammation, and cell death in the lungs were attenuated in AIM-/- mice compared with wild-type (WT) mice in both PPE- and cigarette smoke-induced emphysema models. The PPE-induced increase in MMP-12 was attenuated in AIM-/- mice at both the mRNA and protein levels. According to in vitro experiments using AMs stimulated with cigarette smoke extract, the MMP-12 level was decreased in AIM-/- mice compared with WT mice. This decrease was reversed by the addition of recombinant AIM. Furthermore, an analysis of clinical samples showed that patients with COPD had a higher blood AIM/IgM ratio than healthy smokers. Additionally, the blood AIM/IgM ratio was positively associated with disease severity in patients with COPD. A higher AIM/IgM ratio was also associated with a shorter time to the first COPD exacerbation and higher all-cause and respiratory mortality. CONCLUSIONS: AIM facilitates the development of COPD by upregulating MMP-12. Additionally, a higher blood AIM/IgM ratio was associated with poor prognosis in patients with COPD. TRIAL REGISTRATION: This clinical study, which included nonsmokers, healthy smokers, and smokers with COPD, was approved by the Ethics Committee of the Hokkaido University Hospital (012-0075, date of registration: September 5, 2012). The Hokkaido COPD cohort study was approved by the Ethics Committee of the Hokkaido University School of Medicine (med02-001, date of registration: December 25, 2002).

Clinical characterization of patients with schizophrenia and 16p13.11 duplication: A case series.

BACKGROUND: Chromosome 16p13.11 duplication is a well-known genetic risk factor for schizophrenia (SCZ) (odds ratio = 1.84). However, no case reports focusing on patients with SCZ and 16p13.11 duplication have been published. Therefore, here, we report the detailed clinical cases of four patients with SCZ and 16p13.11 duplication who were identified in our previous whole-genome copy number variant (CNV) study. CASE PRESENTATION: In the four patients with SCZ and 16p13.11 duplication detected by array comparative genomic hybridization, one patient was found to have treatment-resistant SCZ and an additional pathogenic rare CNV. Two of the four patients in this study had environmental risk factors that may have been involved in the development of SCZ. CONCLUSIONS: The results of this case series suggest that a genetic cohort study would be useful for evaluating which genetic and environmental risk factors could better explain the variable expressivity of 16p13.11 duplication. Furthermore, this work could be useful for elucidating the pathophysiology of SCZ.

Feasibility of Seated Stepping and Handshaking as a Cardiopulmonary Exercise Testing: A Pilot Study.

Cardiopulmonary function is usually assessed by cardiopulmonary exercise testing (CPX) using a cycle ergometer (CE-CPX) or a treadmill, which is difficult in patients with lower extremity motor dysfunction. A stepping and handshaking (SHS) exercise has been developed that can be performed safely and easily while sitting on a chair. This study compared peak oxygen uptake (peak V.O2) between CE-CPX and SHS-CPX in healthy adults and investigated the safety and validity of SHS-CPX. Twenty young adults (mean age 27.8 ± 4.4 years) were randomly assigned to perform CE-CPX or SHS-CPX, with the other test to follow 1-2 weeks later. The peak V.O2, respiratory exchange ratio (RER), peak heart rate, blood pressure, and test completion time were compared between CE-CPX and SHS-CPX. All subjects completed the examination and met the criteria for peak V.O2. SHS-CPX and CE-CPX showed a strong correlation with peak V.O2 (r = 0.85, p < 0.0001). The peak V.O2 (40.4 ± 11.3 mL/min/kg vs. 28.9 ± 8.0 mL/min/kg), peak heart rate (190.6 ± 8.9 bpm vs. 172.1 ± 12.6 bpm), and test completion time (1052.8 ± 143.7 s vs. 609.1 ± 96.2 s) were significantly lower in the SHS-CPX (p < 0.0001). There were no adverse events. The peak V.O2 with SHS-CPX was equivalent to about 70% of that with CE-CPX despite the exercise being performed in a sitting position, suggesting its suitability as a submaximal exercise test.

Comparative Study of Muscle Hardness during Water-Walking and Land-Walking Using Ultrasound Real-Time Tissue Elastography in Healthy Young People.

Compared with land-walking, water-walking is considered to be beneficial as a whole-body exercise because of the characteristics of water (buoyancy, viscosity, hydrostatic pressure, and water temperature). However, there are few reports on the effects of exercise in water on muscles, and there is no standard qualitative assessment method for muscle flexibility. Therefore, we used ultrasound real-time tissue elastography (RTE) to compare muscle hardness after water-walking and land-walking. Participants were 15 healthy young adult males (24.8 ± 2.3 years). The method consisted of land-walking and water-walking for 20 min on separate days. The strain ratio of the rectus femoris (RF) and medial head of gastrocnemius (MHGM) muscles were measured before and immediately after walking using RTE to evaluate muscle hardness. In water-walking, the strain ratio significantly decreased immediately after water-walking, with p < 0.01 for RF and p < 0.05 for MHGM, indicating a significant decrease in muscle hardness after water-walking. On the other hand, land-walking did not produce significant differences in RF and MHGM. Muscle hardness after aerobic exercise, as assessed by RTE, was not changed by land walking but was significantly decreased by water walking. The decrease in muscle hardness induced by water-walking was thought to be caused by the edema reduction effect produced by buoyancy and hydrostatic pressure.

Association of serum CC16 levels with eosinophilic inflammation and respiratory dysfunction in severe asthma.

BACKGROUND: There are knowledge gaps in the potential role of Club cell 16-kDa secretory protein (CC16) in severe asthma phenotypes and type 2 inflammation, as well as the longitudinal effect of CC16 on pulmonary function tests and exacerbation risk in epidemiological studies. OBJECTIVE AND METHODS: To assess whether serum CC16 is associated with eosinophilic inflammation in patients with severe asthma. We also examined the effect of this protein on the annual decline in forced expiratory volume in the first second (FEV1) and the risk of exacerbation using a longitudinal approach. We recruited 127 patients with severe asthma from 30 hospitals/pulmonary clinics in Hokkaido, Japan. The least square means and standard error were calculated for T-helper 2 (Th2) biomarkers and pulmonary function test across CC16 tertiles at baseline. We did the same for asthma exacerbation and annual decline in FEV1 with 3 and 5 years' follow-up, respectively. RESULTS: We found that serum CC16 was inversely associated with sputum eosinophils and blood periostin in a dose-response manner. Baseline CC16 and FEV1/forced vital capacity ratio were positively associated in adjusted models (p for trend = 0.008). Patients with the lowest tertile of serum CC16 levels at baseline had a -14.3 mL decline in FEV1 than those with the highest tertile over 5 years of follow-up (p for trend = 0.031, fully adjusted model). We did not find any association of CC16 with exacerbation risk. CONCLUSION: Patients with severe asthma with lower circulatory CC16 had enhanced eosinophilic inflammation with rapid FEV1 decline over time.

The genetic architecture of schizophrenia: review of large-scale genetic studies.

Schizophrenia is a complex and often chronic psychiatric disorder with high heritability. Diagnosis of schizophrenia is still made clinically based on psychiatric symptoms; no diagnostic tests or biomarkers are available. Pathophysiology-based diagnostic scheme and treatments are also not available. Elucidation of the pathogenesis is needed for development of pathology-based diagnostics and treatments. In the past few decades, genetic research has made substantial advances in our understanding of the genetic architecture of schizophrenia. Rare copy number variations (CNVs) and rare single-nucleotide variants (SNVs) detected by whole-genome CNV analysis and whole-genome/-exome sequencing analysis have provided the great advances. Common single-nucleotide polymorphisms (SNPs) detected by large-scale genome-wide association studies have also provided important information. Large-scale genetic studies have been revealed that both rare and common genetic variants play crucial roles in this disorder. In this review, we focused on CNVs, SNVs, and SNPs, and discuss the latest research findings on the pathogenesis of schizophrenia based on these genetic variants. Rare variants with large effect sizes can provide mechanistic hypotheses. CRISPR-based genetics approaches and induced pluripotent stem cell technology can facilitate the functional analysis of these variants detected in patients with schizophrenia. Recent advances in long-read sequence technology are expected to detect variants that cannot be detected by short-read sequence technology. Various studies that bring together data from common variant and transcriptomic datasets provide biological insight. These new approaches will provide additional insight into the pathophysiology of schizophrenia and facilitate the development of pathology-based therapeutics.

X chromosome aneuploidies and schizophrenia: association analysis and phenotypic characterization.

AIM: The aims of the present study were: (i) to examine the association between schizophrenia (SCZ) and 47, XXY or 47, XXX in a large case-control sample; and (ii) to characterize the clinical features of patients with SCZ with these X chromosome aneuploidies. METHODS: To identify 47, XXY and 47, XXX, array comparative genomic hybridization (aCGH) was performed in 3188 patients with SCZ and 3586 controls. We examined the association between 47, XXY and 47, XXX and SCZ in males and females separately using exact conditional tests to control for platform effects. Clinical data were retrospectively examined for patients with SCZ with X chromosome aneuploidies. RESULTS: Of the analyzed samples, 3117 patients (97.8%) and 3519 controls (98.1%) passed our quality control. X chromosome aneuploidies were exclusively identified in patients: 47, XXY in seven patients (0.56%), 47, XXX in six patients (0.42%). Statistical analysis revealed a significant association between SCZ and 47, XXY (P = 0.028) and 47, XXX (P = 0.011). Phenotypic data were available from 12 patients. Treatment-resistance to antipsychotics and manic symptoms were observed in six patients each (four with 47, XXY and two with 47, XXX for both), respectively. Statistical analysis revealed that treatment-resistance to antipsychotics, mood stabilizer use, and manic symptoms were significantly more common in patients with 47, XXY than in male patients without pathogenic copy number variations. CONCLUSION: These findings indicate that both 47, XXY and 47, XXX are significantly associated with risk for SCZ. Patients with SCZ with 47, XXY may be characterized by treatment-resistance and manic symptoms.

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.

Small Peptide Derivatives Within the Carbohydrate Recognition Domain of SP-A2 Modulate Asthma Outcomes in Mouse Models and Human Cells.

Surfactant Protein-A (SP-A) is an innate immune modulator that regulates a variety of pulmonary host defense functions. We have shown that SP-A is dysfunctional in asthma, which could be partly due to genetic heterogeneity. In mouse models and primary bronchial epithelial cells from asthmatic participants, we evaluated the functional significance of a particular single nucleotide polymorphism of SP-A2, which results in an amino acid substitution at position 223 from glutamine (Q) to lysine (K) within the carbohydrate recognition domain (CRD). We found that SP-A 223Q humanized mice had greater protection from inflammation and mucin production after IL-13 exposure as compared to SP-A-2 223K mice. Likewise, asthmatic participants with two copies the major 223Q allele demonstrated better lung function and asthma control as compared to asthmatic participants with two copies of the minor SP-A 223K allele. In primary bronchial epithelial cells from asthmatic participants, full-length recombinant SP-A 223Q was more effective at reducing IL-13-induced MUC5AC gene expression compared to SP-A 223K. Given this activity, we developed 10 and 20 amino acid peptides of SP-A2 spanning position 223Q. We show that the SP-A 223Q peptides reduce eosinophilic inflammation, mucin production and airways hyperresponsiveness in a house dust mite model of asthma, protect from lung function decline during an IL-13 challenge model in mice, and decrease IL-13-induced MUC5AC gene expression in primary airway epithelial cells from asthmatic participants. These results suggest that position 223 within the CRD of SP-A2 may modulate several outcomes relevant to asthma, and that short peptides of SP-A2 retain anti-inflammatory properties similar to that of the endogenous protein.

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.

Effects of obesity on CC16 and their potential role in overweight/obese asthma.

INTRODUCTION: Club cell secretory protein-16 (CC16) is a major anti-inflammatory protein expressed in the airway; however, the potential role of CC16 on overweight/obese asthma has not been assessed. In this study, we examined whether obesity reduces airway/circulatory CC16 levels using experimental and epidemiological studies. Then, we explored the mediatory role of CC16 in the relationship of overweight/obesity with clinical asthma measures. METHODS: Circulating CC16 levels were assessed by ELISA in three independent human populations, including two groups of healthy and general populations and asthma patients. The percentage of cells expressing club markers in obese vs. non-obese mice and human airways was determined by immunohistochemistry. A causal mediation analysis was conducted to determine whether circulatory CC16 acted as a mediator between overweight/obesity and clinical asthma measures. RESULTS: BMI was significantly and monotonously associated with reduced circulating CC16 levels in all populations. The percentage of CC16-expressing cells was reduced in the small airways of both mice and humans with obesity. Finally, mediation analysis revealed significant contributions of circulatory CC16 in the association between BMI and clinical asthma measures; 21.8% of its total effect in BMI's association with airway hyperresponsiveness of healthy subjects (p = 0.09), 26.4% with asthma severity (p = 0.030), and 23% with the required dose of inhaled corticosteroid (p = 0.042). In logistic regression analysis, 1-SD decrease in serum CC16 levels of asthma patients was associated with 87% increased odds for high dose ICS requirement (p < 0.001). CONCLUSIONS: We demonstrate that airway/circulating CC16, which is inversely associated with BMI, may mediate development and severity in overweight/obese asthma.

Sequencing of selected chromatin remodelling genes reveals increased burden of rare missense variants in ASD patients from the Japanese population.

Chromatin remodelling is an important process in neural development and is related to autism spectrum disorder (ASD) and schizophrenia (SCZ) aetiology. To further elucidate the involvement of chromatin remodelling genes in the genetic aetiology of ASD and SCZ in the Japanese population, we performed a case-control study. Targeted sequencing was conducted on coding regions of four BAF chromatin remodelling complex genes: SMARCA2, SMARCA4, SMARCC2, and ARID1B in 185 ASD, 432 SCZ patients, and 517 controls. 27 rare non-synonymous variants were identified in ASD and SCZ patients, including 25 missense, one in-frame deletion in SMRACA4, and one frame-shift variant in SMARCC2. Association analysis was conducted to investigate the burden of rare variants in BAF genes in ASD and SCZ patients. Significant enrichment of rare missense variants in BAF genes, but not synonymous variants, was found in ASD compared to controls. Rare pathogenic variants indicated by in silico tools were significantly enriched in ASD, but not statistically significant in SCZ. Pathogenic-predicted variants were located in disordered binding regions and may confer risk for ASD and SCZ by disrupting protein-protein interactions. Our study supports the involvement of rare missense variants of BAF genes in ASD and SCZ susceptibility.

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.

Case Report: Hereditary Fibrosing Poikiloderma With Tendon Contractures, Myopathy, and Pulmonary Fibrosis (POIKTMP) Presenting With Liver Cirrhosis and Steroid-Responsive Interstitial Pneumonia.

Background: Hereditary fibrosing poikiloderma with tendon contractures, myopathy, and pulmonary fibrosis (POIKTMP) is an extremely rare disease caused by mutations in FAM111B, and only approximately 30 cases have been reported worldwide. Some patients develop interstitial pneumonia, which may lead to progressive pulmonary fibrosis and poor prognosis. However, no effective treatment for interstitial pneumonia associated with POIKTMP has been reported. Here, we report an autopsy case of POIKTMP, wherein interstitial pneumonia was improved by corticosteroids. Case Presentation: A 44-year-old Japanese man was referred to our hospital due to poikiloderma, hypotrichosis, and interstitial pneumonia. He developed progressive poikiloderma and muscle weakness since infancy. He also had tendon contractures, short stature, liver cirrhosis, and interstitial pneumonia. Mutation analysis of FAM111B revealed a novel and de novo heterozygous missense mutation, c.1886T > G (p(Phe629Cys)), through which we were able to diagnose the patient with POIKTMP. 3 years after the POIKTMP diagnosis, interstitial pneumonia had worsened. After 2 weeks of administrating 40 mg/day of prednisolone, his symptoms and lung shadows improved. However, he subsequently developed severe hepatic encephalopathy and eventually died of respiratory failure due to bacterial pneumonia and pulmonary edema. Autopsy revealed an unclassifiable pattern of interstitial pneumonia, as well as the presence of fibrosis and fatty degeneration in several organs, including the liver, kidney, skeletal muscle, heart, pancreas, and thyroid. Conclusions: We report a case of POIKTMP in which interstitial pneumonia was improved by corticosteroids, suggesting that corticosteroids could be an option for the treatment of interstitial pneumonia associated with this disease.