De Novo Sequence and Copy Number Variants Are Strongly Associated with Tourette Disorder and Implicate Cell Polarity in Pathogenesis

We previously established the contribution of de novo damaging sequence variants to Tourette disorder (TD) through whole-exome sequencing of 511 trios. Here, we sequence an additional 291 TD trios and analyze the combined set of 802 trios. We observe an overrepresentation of de novo damaging variants in simplex, but not multiplex, families; we identify a high-confidence TD risk gene, CELSR3 (cadherin EGF LAG seven-pass G-type receptor 3); we find that the genes mutated in TD patients are enriched for those related to cell polarity, suggesting a common pathway underlying pathobiology; and we confirm a statistically significant excess of de novo copy number variants in TD. Finally, we identify significant overlap of de novo sequence variants between TD and obsessive-compulsive disorder and de novo copy number variants between TD and autism spectrum disorder, consistent with shared genetic risk.ope

A Descriptive Study on the Civil Lawsuits of Medical Malpractice Occurred during Psychiatric Ward Treatment

Objective: Medical accidents have resulted in actual harm for patients, been costly for health care system, and diminished trust for both patients and practitioners. The present study analyzed malpractice claims related to accidents in psychiatric inpatient units. Methods: This study analyzed defendants, cases and plaintiffs or patients characteristics, degrees of injury, and types of accidents in 85 civil malpractice suits filed from 2005 to 2015 with a focus on the methods and locations of suicides. Results: Most defendants were psychiatrists (n=43). Of the 85 cases, 56 (65.9%) were decided in favor of the plaintiff, most commonly on the grounds of negligence and violation of sound facility management principles. The most common diagnosis of patients was schizophrenia (n=31). The damages were deaths in 52 cases and injuries or other damages in the remaining 33 cases. The most common accident was suicide (n=28), followed by escape attempts (n=15). The most common suicide method was hanging (n=21), which was usually committed in the private room using objects like door handles. Conclusion: To reduce medical accidents, medical staff should monitor high-risk patients closely and constantly. Sufficient numbers of well-trained personnel are required to meet this standard. Reducing environmental hazards such as removing anchor points and installing door locking systems will improve patient safety.ope

ANXIOUS-DEPRESSIVE ATTRIBUTES TO SUICIDAL IDEA OF ADOLESCENTS

Objectives：This study was aimed at examining the emotional predictors of adolescent suicidal ideas in a community. Methods：The subjects were 1909 middle and high school students(936 males, 973 females) in Koyang-shi. We evaluated all subjects using Center for Epidemiologic Study for Depression(CES-D), Revised Children's Manifest Anxiety Scale(RCMAS), Korean-Youth Self Report(K-YSR), Psychological Self-1 of Offer's Self Image Questionnaire(PS-1 of OSIQ) and Suicide Ideation Questionnaire (SIQ). We compared the PS-1 of OSIQ scores of Anxious-depressive group(above cut-off points of CES-D, RCMAS and K-YSR) to those of control group, and conducted correlation analysis and stepwise multiple regression analysis to all subjects. Results：The number of anxious-depressive group was 126(6.58%) among 1909 subjects with significant gender difference(M：F ratio 1：1.5). Both PS-1 of OSIQ and SIQ scores were significantly higher in Anxious-depressive group than in control group. There were significant correlations among the scales：CES-D, RCMAS, A/D of K-YSR, PS-1 of OSIQ and SIQ. Through stepwise multiple regression analysis, we found that significant predictors of suicidal idea were CES-D, RCMAS and A/D of K-YSR. Conclusion：Anxious-depressive adolescents may be the high-risk group for suicidality and need preventive interventions of suicidality in a community.ope

Child Sexual Abuse and Nation-Funded Child Sexual Abuse Protection Center (Sunflower Center)

Child sexual abuse (CSA) is one of the most crucial health and social problems. CSA has complicated issues related to mental, physical, sociocultural and legal perspectives, and social welfare in children and their families. Several psychopathologies following CSA have been reported as an immediate or short-term sequela, including fearfulness, anxiety-related symptoms, dissociation, and depression. Further, victimized adolescents have been reported to exhibit increased multiple problematic behaviors, such as suicidality, sexual dissatisfaction, uncontrolled sexual behaviors, aggression, and illegal drugs or substance abuse, as well as elevated risk of re-victimization. Nation-funded Sunflower Centers have provided comprehensive services for victims of sexual abuse since 2004. It is conducted in the form of one-stop services by psychiatrists, psychologists, social workers, family therapists, art therapists, police officers, and counseling lawyers at 41 Sunflower Centers. The following issues for child welfare are further elaborated: 1) standardization of practice guidelines to manage trauma-related psychopathology through persistent government-lead research and investments for victims of CSA, 2) establishment of a nation-based agenda to manage and prevent CSA, 3) establishment of a multi-center nation-based cohort system for research and management of victims of CSA and their families, 4) governmental integration of Sun Flower service for CSA and services for child protection and abuse.ope

Aberrant Neural Activation Underlying Idiom Comprehension in Korean Children with High Functioning Autism Spectrum Disorder

PURPOSE: Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by social communication impairments and repetitive behaviors or restricted interests. Impaired pragmatic language comprehension is a universal feature in individuals with ASD. However, the underlying neural basis of pragmatic language is poorly understood. In the present study, we examined neural activation patterns associated with impaired pragmatic language comprehension in ASD, compared to typically developing children (TDC). MATERIALS AND METHODS: Functional magnetic resonance imaging (fMRI) was applied to 15 children with ASD and 18 TDC using the Korean pragmatic language task. RESULTS: Children with ASD were less accurate than TDC at comprehending idioms, particularly when they were required to interpret idioms with mismatched images (mismatched condition). Children with ASD also showed different patterns of neural activity than TDC in all three conditions (neutral, matched, and mismatched). Specifically, children with ASD showed decreased activation in the right inferior frontal gyrus (IFG) (Brodmann area 47) in the mismatched condition, compared with TDC (IFG; t(31)=3.17, p<0.001). CONCLUSION: These results suggest that children with ASD face difficulties in comprehending pragmatic expressions and apply different pragmatic language processes at the neural level.ope

A Cohort Study of Children and Adolescents Victims with Sexual Abuse in Korea and Their Initial Assessment Results

Objectives : The goals of the study are how to establish the cohort systems for the children and adolescents victims with sexual abuse in Korea and to identify the risk and protective factors that influence mental health in child sexual abuse (CSA). This is initial assessment data based on the analysis of cohort variables for baseline evaluation of subjects. Methods : We constructed the cohort systems for CSA victims recruited by Seoul Sunflower Children Center, CSA victims protection center. The initial assessment data which consisted of demographic and psychological inventories of CSA victims and their parents/families, psychiatric diagnoses were the results of statistical analysis of 65 subjects under 19 years old for 3 years 7 months. Results : The initial data were followings : female participants, N=56; mean age, 11.6 (SD=4.5); the most sexual assault, molestation 71.8%; victims, family and acquaintance 87.1%; 61.5% of the subjects diagnosed with psychiatric disorder; 29.2% diagnosed with PTSD and 23.1% diagnosed with depression. Mean duration for abuse to report is 1.5 years. Mean score of IES-R-K, TSCYC-avoidant and CBCL-problematic behavior were increased above clinical cut-off. Conclusions : CSA victims tend to have high risks in mental health problem. The cohort study could provide the risk and protective factors of CSA in mental health, and construct the predictive model for mental illness in Korea.ope

Psychosocial Factors and Psychiatric Disorder in Childhood Chronic Abdominal Pain

Childhood chronic abdominal pain usually doesn’t have an organic etiology. It may cause social impairment and emotional distress in children as well as their families. In view of cognitive and behavioral aspect, passive coping style, maladaptive social modeling, and reinforced secondary gain could contribute to the development and maintenance of pediatric somatization. Integrative etiological model includes biological factors due to the enteric sensitization process, psychosocial factors which encompass family influences, psychodevelomental vulnerability, and life event-related stress. These factors interact with each other and manifest as various psychosomatic symptoms. In the treatment of childhood chronic abdominal pain, multimodal treatment program, which includes cognitive behavioral therapeutic methods, emotional support, family education, selective serotonin reuptake inhibitor, and so on, is known to be most effectiveope

Investigation of previously implicated genetic variants in chronic tic disorders: a transmission disequilibrium test approach

Genetic studies in Tourette syndrome (TS) are characterized by scattered and poorly replicated findings. We aimed to replicate findings from candidate gene and genome-wide association studies (GWAS). Our cohort included 465 probands with chronic tic disorder (93% TS) and both parents from 412 families (some probands were siblings). We assessed 75 single nucleotide polymorphisms (SNPs) in 465 parent-child trios; 117 additional SNPs in 211 trios; and 4 additional SNPs in 254 trios. We performed SNP and gene-based transmission disequilibrium tests and compared nominally significant SNP results with those from a large independent case-control cohort. After quality control 71 SNPs were available in 371 trios; 112 SNPs in 179 trios; and 3 SNPs in 192 trios. 17 were candidate SNPs implicated in TS and 2 were implicated in obsessive-compulsive disorder (OCD) or autism spectrum disorder (ASD); 142 were tagging SNPs from eight monoamine neurotransmitter-related genes (including dopamine and serotonin); 10 were top SNPs from TS GWAS; and 13 top SNPs from attention-deficit/hyperactivity disorder, OCD, or ASD GWAS. None of the SNPs or genes reached significance after adjustment for multiple testing. We observed nominal significance for the candidate SNPs rs3744161 (TBCD) and rs4565946 (TPH2) and for five tagging SNPs; none of these showed significance in the independent cohort. Also, SLC1A1 in our gene-based analysis and two TS GWAS SNPs showed nominal significance, rs11603305 (intergenic) and rs621942 (PICALM). We found no convincing support for previously implicated genetic polymorphisms. Targeted re-sequencing should fully appreciate the relevance of candidate genes.ope

Synaptic processes and immune-related pathways implicated in Tourette syndrome

Tourette syndrome (TS) is a neuropsychiatric disorder of complex genetic architecture involving multiple interacting genes. Here, we sought to elucidate the pathways that underlie the neurobiology of the disorder through genome-wide analysis. We analyzed genome-wide genotypic data of 3581 individuals with TS and 7682 ancestry-matched controls and investigated associations of TS with sets of genes that are expressed in particular cell types and operate in specific neuronal and glial functions. We employed a self-contained, set-based association method (SBA) as well as a competitive gene set method (MAGMA) using individual-level genotype data to perform a comprehensive investigation of the biological background of TS. Our SBA analysis identified three significant gene sets after Bonferroni correction, implicating ligand-gated ion channel signaling, lymphocytic, and cell adhesion and transsynaptic signaling processes. MAGMA analysis further supported the involvement of the cell adhesion and trans-synaptic signaling gene set. The lymphocytic gene set was driven by variants in FLT3, raising an intriguing hypothesis for the involvement of a neuroinflammatory element in TS pathogenesis. The indications of involvement of ligand-gated ion channel signaling reinforce the role of GABA in TS, while the association of cell adhesion and trans-synaptic signaling gene set provides additional support for the role of adhesion molecules in neuropsychiatric disorders. This study reinforces previous findings but also provides new insights into the neurobiology of TS.ope

Investigation of gene-environment interactions in relation to tic severity

Tourette syndrome (TS) is a neuropsychiatric disorder with involvement of genetic and environmental factors. We investigated genetic loci previously implicated in Tourette syndrome and associated disorders in interaction with pre- and perinatal adversity in relation to tic severity using a case-only (N = 518) design. We assessed 98 single-nucleotide polymorphisms (SNPs) selected from (I) top SNPs from genome-wide association studies (GWASs) of TS; (II) top SNPs from GWASs of obsessive-compulsive disorder (OCD), attention-deficit/hyperactivity disorder (ADHD), and autism spectrum disorder (ASD); (III) SNPs previously implicated in candidate-gene studies of TS; (IV) SNPs previously implicated in OCD or ASD; and (V) tagging SNPs in neurotransmitter-related candidate genes. Linear regression models were used to examine the main effects of the SNPs on tic severity, and the interaction effect of these SNPs with a cumulative pre- and perinatal adversity score. Replication was sought for SNPs that met the threshold of significance (after correcting for multiple testing) in a replication sample (N = 678). One SNP (rs7123010), previously implicated in a TS meta-analysis, was significantly related to higher tic severity. We found a gene-environment interaction for rs6539267, another top TS GWAS SNP. These findings were not independently replicated. Our study highlights the future potential of TS GWAS top hits in gene-environment studies.ope