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

Abstract

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.

Case reports of two siblings with autism spectrum disorder and 15q13.3 deletions

“…Copy number variants (CNVs) have been implicated in psychiatric and neurodevelopmental disorders. 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 Specifically, 15q13.3 deletions have been identified as associated with intellectual disability (ID), autism spectrum disorder (ASD), schizophrenia (SCZ), attention deficit hyperactivity disorder (ADHD), and mood disorder. 9 , 10 , 11 , 12 15q13.3 deletions are typically inherited (85.4%) and disproportionately of maternal origin.…”

Editorial: Molecular pathology in psychiatric diseases: frontiers of postmortem brain research

“…This increase is a result of reevaluating the significance of brain pathology in schizophrenia, as the antipsychotic mechanism of action highlights the brain regions such as the midbrain, striatum, limbic system, and cortical tracts involved in the dopamine neurotransmitter system, and progress of structural brain imaging research using CT and MRI, and functional brain imaging research using SPECT and PET. Thus, postmortem brain research on schizophrenia and bipolar disorder is currently very active, and due to recent remarkable technological innovations in the field of basic neuroscience, examinations at the molecular level, such as analysis of mRNA (1), proteins (2-4) and lipids (5) expressed in the brain, and brain-specific genomic polymorphisms, such as CNV (6) and DNA methylation (7) are rapidly being conducted. Against the background of these multifaceted developments in neuroscience and the ability to perform comprehensive analyses of small amounts of tissue samples, postmortem brain studies on psychiatric disorders have shifted from the traditional role of validating the results obtained in basic neuroscience studies to a more exploratory role of adding new findings and providing feedback for other approaches.…”

Do autism spectrum traits run in severe anorexia nervosa?

“…Kushima et al 4 conducted a high‐resolution CNV analysis (>10 kb) of 71 female patients with severe ED and 1045 controls, and they identified a significant association between neurodevelopmental disorder–associated CNVs (NDD‐CNVs) and EDs (odds ratio = 4.69). Many of the NDD‐CNVs in patients with ED affected genes related to synaptic function.…”

“…To date, a couple of CNV studies with large recurrent CNVs (>500 kb) 5 in AN have been published, although none of the well‐established pathogenic CNVs associated with AN were observed. In Kushima's study, 4 the contribution of small CNVs in EDs was explored. Interestingly, CNTN4 , one of the CNVs identified in their study, is a risk gene for neuropsychiatric disorders, as it modulates hippocampal synaptic plasticity and behavior.…”