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.

Contribution of copy number variations to the risk of severe eating disorders.

AIM: Eating disorders (EDs) are complex, multifactorial psychiatric conditions. Previous studies identified pathogenic copy number variations associated with NDDs (NDD-CNVs) in ED patients. However, no statistical evidence for an association between NDD-CNVs and EDs has been demonstrated. Therefore, we examined whether NDD-CNVs confer risk for EDs. METHODS: Using array comparative genomic hybridization (aCGH), we conducted a high-resolution CNV analysis of 71 severe female ED patients and 1045 female controls. According to the American College of Medical Genetics guidelines, we identified NDD-CNVs or pathogenic/likely pathogenic CNVs in NDD-linked loci. Gene set analysis was performed to examine the involvement of synaptic dysfunction in EDs. Clinical data were retrospectively examined for ED patients with NDD-CNVs. RESULTS: Of the samples analyzed with aCGH, 70 severe ED patients (98.6%) and 1036 controls (99.1%) passed our quality control filtering. We obtained 189 and 2539 rare CNVs from patients and controls, respectively. NDD-CNVs were identified in 10.0% (7/70) of patients and 2.3% (24/1036) of controls. Statistical analysis revealed a significant association between NDD-CNVs and EDs (odds ratio = 4.69, P = 0.0023). NDD-CNVs in ED patients included 45,X and deletions at KATNAL2, DIP2A, PTPRT, RBFOX1, CNTN4, MACROD2, and FAM92B. Four of these genes were related to synaptic function. In gene set analysis, we observed a nominally significant enrichment of rare exonic CNVs in synaptic signaling in ED patients (odds ratio = 2.55, P = 0.0254). CONCLUSION: Our study provides the first preliminary evidence that NDD-CNVs may confer risk for severe EDs. The pathophysiology may involve synaptic dysfunction.

Decline of Plasma Concentrations of Interleukin-18 in Severely Malnourished Patients with Anorexia Nervosa: Exploratory Analysis.

Multiple studies on the dynamics of inflammatory cytokines in patients with anorexia nervosa (AN) have been published, although results are not consistent among reports. Thus the pathophysiologic roles of these cytokines are not clear. We performed an exploratory analysis that included (1) comparisons of plasma interleukin-18 (IL-18) concentrations between patients with AN (n = 21) and healthy controls (n = 39), and (2) correlations between body mass index (BMI) and IL-18 concentrations in both groups, exploring the relationship between malnourishment and IL-18. Plasma IL-18 levels were significantly decreased in patients with AN compared with controls. Plasma IL-18 levels correlated to BMI in controls, but not in patients with AN. These results suggest that a decline in plasma IL-18 levels in patients with AN is not only due to malnourishment, but other pathophysiologic changes as well. IL-18 has a role in the brain's reaction to sadness and chronic stress. Therefore, decreased levels of IL-18 may commonly occur in patients with chronic AN.

Regional decrease in gray matter volume is related to body dissatisfaction in anorexia nervosa.

Anorexia nervosa (AN) is a psychiatric disorder, in which the prognosis for some patients is poor. The etiology and effective treatments for AN have not been established. We examined morphometric changes in the brain of AN and clarified how the changes were associated with symptoms and pathophysiology. We enrolled 52 participants: 7 with the restrictive type of AN, 13 with the binge-eating/purging type, 3 with eating disorder not otherwise specified, and 29 healthy controls. Participants underwent T1-weighted MRI. Group differences between patients and controls in gray matter volume (GMV) were analyzed using voxel-based morphometry. Age and body mass index (BMI) were considered covariates. Correlations between regional GMVs and drive for thinness and body dissatisfaction were examined. Patients had decreased GMV in the superior/middle temporal gyrus (STG/MTG), pulvinar, and superior frontal gyrus after correction for age and BMI, and in the STG/MTG, middle frontal gyrus, and cingulate after correction for age. A correlational group difference was detected for body dissatisfaction and GMV in the STG. Our findings suggest that decreased GMV in the STG is related to body dissatisfaction that could come from impaired visuospatial perception, together with GMV decreases in several regions, which may be involved in development of AN.

Risk factors for elevated liver enzymes during refeeding of severely malnourished patients with eating disorders: a retrospective cohort study.

BACKGROUND: There are few previous reports regarding the cause and evolution of liver injury in patients with anorexia nervosa (AN) during the refeeding process, and its management remains controversial. This study aimed to determine the risk factors for elevated liver enzymes during refeeding and their effect on the therapeutic process in severely malnourished patients with eating disorders. METHODS: In a retrospective cohort study of 167 female inpatients in a single hospital from January 2004 to March 2015, 67 who had normal alanine aminotransferase (ALT) levels on admission were divided into two groups according to the presence or absence of elevated ALT levels during refeeding, and then compared. RESULTS: The median age and body mass index (BMI) of the patients on admission were 22 [interquartile range (IQR), 16-33] years and 12.2 (IQR, 11.1-13.0) kg/m2, respectively. Compared with their cohorts, significantly more patients in the early onset age group (<15 years old) had elevated ALT levels during refeeding (67% vs. 33%, p = 0.033), as did patients with longer median time to nadir BMI (3.0 vs. 0 days, p = 0.03). In addition, onset age [odds ratio (OR): 0.274; 95% confidence interval (CI): 0.077-0.981; p = 0.047] and time to nadir BMI (OR: 1.271; 95% CI: 1.035-1.56; p = 0.022) were significantly associated with the odds of elevated ALT levels during refeeding. CONCLUSIONS: The results of this study suggest that early age at onset may be a potential risk factor for elevated ALT levels during refeeding in severely malnourished patients with eating disorders. Furthermore, elevated ALT levels during refeeding were significantly associated with delay in the start of weight gain. No significant relationship was found between the amount of initial prescribed calories and elevated ALT levels during refeeding. The median time to maximum ALT was 27 (IQR, 21-38) days after the refeeding process started.

Association of Beck Depression Inventory score and Temperament and Character Inventory-125 in patients with eating disorders and severe malnutrition.

The authors investigated the association between personality and physical/mental status in malnourished patients with eating disorders. A total of 45 patients with anorexia nervosa, avoidant/restrictive food intake disorder, and other specified feeding or eating disorders were included and compared with 39 healthy controls. Personality characteristics and severity of depression were assessed using the Temperament and Character Inventory-125 and Beck's Depression Inventory. Depression correlated with harm avoidance and self-directedness in both cases and controls. Body mass index did not correlate with personality in either group. These findings should be verified by longitudinal studies with higher weight/weight recovered patients.

Social insecurity in relation to orbitofrontal activity in patients with eating disorders: a near-infrared spectroscopy study.

BACKGROUND: Functional neuroimaging techniques are widely used to elucidate changes in brain activity, and various questionnaires are used to investigate psychopathological features in patients with eating disorders (ED). It is well known that social skills and interpersonal difficulties are strongly associated with the psychopathology of patients with ED. However, few studies have examined the association between brain activity and social relationships in patients with ED, particularly in patients with extremely low body weight. METHODS: In this study, 22-channel near-infrared spectroscopy was used to quantify regional hemodynamic changes during a letter fluency task (LFT) in 20 female patients with ED with a mean body mass index of 14.0 kg/m(2) and 31 female controls (CTLs). Symptoms were assessed using the Eating Disorder Inventory-2 and Beck Depression Inventory. We hypothesized that frontal activity in patients with ED would be lower than in CTLs and would show different correlations with psychopathological features compared with CTLs. RESULTS: The LFT performance and score on the social insecurity subscale of the Eating Disorder Inventory-2 were significantly higher in the ED group than in the CTL group. The mean change in oxygenated hemoglobin (oxy-Hb) in bilateral frontal regions during the LFT was significantly smaller in the ED group than in the CTL group. Social insecurity score was positively correlated with the concentration of oxy-Hb in the bilateral orbitofrontal cortex in the ED group but not in the CTL group. CONCLUSIONS: These results suggest that activity of the orbitofrontal cortex is associated with social insecurity and disturbed in patients with ED. Therefore, disturbed orbitofrontal cortex activity may underlie the lack of insight and social isolation that is characteristic of patients with ED.