Quality of Life for Adults with Prader-Willi Syndrome in Residential Group Homes.

Background: Strict regimens of restricted caloric intake and daily physical exercise are life-saving in Prader-Willi syndrome (PWS) but are extremely challenging in home environments. PWS-specialized hostels (SH) succeed in preventing morbid obesity and in coping with behavioral disorders; however, effects of restricted living environments on quality of life (QOL) have not been described. Evidence on QOL is critical for clinicians involved in placement decisions. Methods: We examined the impact of living in SH versus at home or in non-specialized hostels (H and NSH) on QOL, behavior, and health parameters. All 58 adults (26 males) followed-up in the National Multidisciplinary Clinic for PWS were included: 33 resided in SH, 18 lived at home, and 7 lived in NSH. Questionnaires were administered to primary caregivers to measure QOL, and data were obtained from the medical records. Results: The H and NSH group were compared with those for adults in SH. Despite strict diet and exercise regimens, QOL was similar for both groups. Eight-year follow-up showed that food-seeking behavior decreased in SH but increased in H and NSH. BMI, cholesterol, and triglyceride levels were lower in SH. Conclusion: Our results suggest that living in SH is associated with benefits for physical health and behavior without negatively affecting QOL.

Decreased mononuclear cell NR3C1 SKA2 and FKPB5 expression levels among adult survivors of suicide bombing terror attacks in childhood are associated with the development of PTSD.

Life threatening trauma and the development of PTSD during childhood, may each associate with transcriptional perturbation of immune cell glucocorticoid reactivity, yet their separable longer term contributions are less clear. The current study compared resting mononuclear cell gene expression levels of the nuclear receptor, subfamily 3, member 1 (NR3C1) coding the glucocorticoid receptor, its trans-activator spindle and kinetochore-associated protein 2 (SKA2), and its co-chaperon FKBP prolyl isomerase 5 (FKBP5), between a cohort of young adults first seen at the Hadassah Emergency Department (ED) after surviving a suicide bombing terror attack during childhood, and followed longitudinally over the years, and matched healthy controls not exposed to life threatening trauma. While significant reductions in mononuclear cell gene expression levels were observed among young adults for all three transcripts following early trauma exposure, the development of subsequent PTSD beyond trauma exposure, accounted for a small but significant portion of the variance in each of the three transcripts. Long-term perturbation in the expression of immune cell glucocorticoid response transcripts persists among young adults who develop PTSD following life threatening trauma exposure in childhood, denoting chronic dysregulation of immune stress reactivity.

The importance of gynecological examination in adolescent girls and adult women with Prader-Willi syndrome.

Current published guidelines for routine care of women with Prader-Willi syndrome (PWS) do not include recommendations for gynecologic examinations. We describe our experience with gynecological examinations in women with PWS and offer recommendations for routine health care for these patients. Data were collected on all 41 PWS females ages ≥12 year, followed in our national Israeli multidisciplinary clinic between the years 2011 and 2022. Menstrual data and findings on external gynecological examination, including evaluation of the vulva and hymen were recorded at yearly visits. During the gynecological evaluation the topic of sexual education was discussed. Pelvic ultrasound, specifically for antral follicular count, was performed for those visiting the clinic during 2020-2022. Blood samples for luteinizing hormone (LH), follicular stimulating hormone (FSH), and estradiol were obtained routinely and DEXA scans for bone density were done when indicated. Of the 41 women, (median age at start of follow-up 17 years, range [12.3-39], BMI 30.4 kg/m2 [IQR 23.5-37.1]), 39 women agreed to external gynecological examination. Eleven women (27%) had spontaneous menses, with menarche at the age of 14 to as late as 31 years. The hymen was intact in all except one. Poor hygiene was observed in eight women, three women with vulvovaginitis, and five with irritated vulva related to poor hygiene. Gynecological ultrasound was performed in 27 women. In 22, endometrial thickness was less than 5 mm. The median antral follicular count (AFC) was 6 (<10th percentile for age). No correlation between AFC and menstruation or BMI was found. Mean FSH level was 5.7 ± 3.6 IU, LH was 2.29 ± 2.23, and estradiol was 128 ± 76 pmol/L. Data on DEXA measurements were available in 25 women aged 16-39. Median spine T score was -1.3 (range between 0.5 and -3.7), and hip T score was -1.2 (range between 0.8 and -3.3). A negative correlation was found between endometrial thickness and the presence of osteopenia or osteoporosis (r = -0.5, p = 0.013). Despite our recommendations, only eight of 14 women agreed to hormonal treatment or contraception. One woman who received treatment had a thromboembolic event. Routine health care for women with PWS should include gynecological examinations. The gynecological evaluation should include external genital examination, assessment of hygiene, obtaining a blood sample for hormone levels, and documenting a history of sexual experience or sexual abuse. Hormonal treatment or contraception should be offered when appropriate.

A Cross Sectional Study to Identify Traumatic Stress, Medical Phobia and Non-Adherence to Medical Care among Very Young Pediatric Patients.

After a traumatic medical event, such as surgery or hospitalization, a child may develop a phobia of medical care, sometimes preventing future medical adherence and impairing recovery. This study examined the correlation of Pediatric Medical Traumatic Stress (PMTS) on the development of Medical Phobia (MP) and subsequent treatment adherence. We enrolled 152 parents of children aged 1-6 hospitalized in a surgical ward. During hospitalization, parents completed questionnaires that identified post-traumatic stress symptoms. Four months post hospitalization, parents completed questionnaires on post-traumatic stress, medical phobia, psychosocial variables and medical adherence. We found a positive correlation between PMTS and MP and low adherence to medical treatment. In addition, MP mediated the relationship between PMTS severity and adherence, indicating that PMTS severity is associated with stronger medical phobia, and lower pediatric adherence to medical treatment. Our findings suggest that medical phobia serves as an essential component of PMTS. It is important to add medical phobia to medical stress syndrome definition. In addition, as MP and PMTS are involved in the rehabilitation and recovery process and subsequent success, it is an important aspect of treatment adherence.

Intercultural Differences in the Development of Pediatric Medical Traumatic Stress (PMTS) in Children Following Surgical Hospitalization.

BACKGROUND: Illness, surgery and surgical hospitalization are significant stressors for children. Some children who experience such a medical event may develop Pediatric Medical Traumatic Stress (PMTS). PMTS affects physical recovery, and many areas and functions in children's lives, both short- and long-term. The aim of the study is to examine the difference in the rate of PMTS between the Arab and Jewish populations and the difference in risk factors for the development of this syndrome. METHOD: The study involved 252 parents of children aged 1-6 who were hospitalized in the surgical ward of Hadassah Medical Center. During hospitalization, parents completed questionnaires to identify risk factors for the development of PMTS. At 3 months from the time of discharge, the children's level of PMTS was measured. RESULTS: The rate of children diagnosed with PMTS among Arab children was significantly higher than the rate in the Jewish population. The affiliation to an ethnic group affected different socioeconomic, demographic, social, linguistic and cultural background variables, which in turn affected the emergence of PMTS. CONCLUSION: The study emphasizes the nature of PMTS at the intercultural level, which can be an important source for theoretically understanding both the disorder and culture, as well as for clinical implications in developing population-sensitive treatment.

Parental Psychological Flexibility as a Mediating Factor of Post-Traumatic Stress Disorder in Children after Hospitalization or Surgery.

BACKGROUND: Illness, surgery, and surgical hospitalization are significant stressors for children. Children exposed to such medical events may develop post-traumatic medical syndrome (PMTS, pediatric medical traumatic stress) that could slow their physical and emotional recovery. OBJECTIVE: This study examined the relationship between the level of parental psychological resilience and the development of PMTS in young children. METHOD: We surveyed 152 parents of children aged 1-6 who were admitted to the pediatric surgery department. Parents completed questionnaires in two phases. In the first phase, one of the parents completed the Acceptance and Action Questionnaire (AAQ-ll) and the Parental Psychological Flexibility (PPF) Questionnaire. In the second phase, about three months after discharge, the same parent completed the Young Child PTSD (Post Traumatic Stress Disorder) Checklist (YCPC) and the UCLA (Los Angeles, CA, USA) PTSD Reaction Index for DSM-5 Parent/Caregiver Version for Children Age 6 Years and Younger Evaluating Post-traumatic Disorder. In addition, the parent completed a Posttraumatic Stress Diagnostic Scale (PDS) questionnaire to assess the existence of post-traumatic symptoms in the parents. RESULTS: The findings indicate that (1) a parent's psychological flexibility is significantly associated with the level of personal distress (r = -0.45, p < 0.001), (2) a parents' level of distress is significantly correlated with the child's level of PTMS, and (3) a parent's level of psychological flexibility is a significant mediating factor between the level of parental post-traumatic distress and the child's level of PTMS. CONCLUSIONS: A parent's psychological flexibility may act as a protective factor against the development of the child's mental distress after hospitalization or surgery.

Syndrome-Related Risk Factors for Sexual Abuse: The Example of Prader-Willi Syndrome.

Many genetic disorders associated with intellectual disability are characterized by unique behavioral phenotypes which may have serious psychological consequences such as increasing the risk for sexual abuse (SA). Prader-Willi Syndrome (PWS), a severe neurogenetic syndrome with uncontrollable hyperphagia and high threshold for pain, is an excellent example of this issue. The absence of reports on SA in PWS highlights the lack of awareness to the topic. Our aim was to report on SA in individuals with PWS, describe its unique characteristics, and offer recommendations for its prevention. Caregivers of all individuals with genetically confirmed PWS living in the only two residential facilities designated for PWS in Israel were interviewed for a history of sexual behavior and abuse, and medical data were collected from their files. SA was reported in a quarter of the sample. In most of the cases (78%), food reward was used by the perpetrators to attract their victims. Age at SA ranged from 11 to 29 years. Most of the individuals did not disclose the event and some continued to initiate inappropriate sexual activity to obtain food. Characteristics unique to PWS, such as food-seeking behaviors and high threshold for pain, likely contribute to the risk for SA. These findings suggest that syndrome-specific programs for SA prevention should be considered for individuals with any genetic syndrome with behavioral problems that may increase SA risk.

Resting mononuclear cell NR3C1 and SKA2 expression levels predict blunted cortisol reactivity to combat training stress among elite army cadets exposed to childhood adversity.

Childhood adversity (CA) may alter reactivity to stress throughout life, increasing risk for psychiatric and medical morbidity, yet long-term correlates of milder CA levels among high functioning healthy adolescents are less studied. The current study examined the prevalence and impact of CA exposure among a cohort of healthy motivated elite parachute unit volunteers, prospectively assessed at rest and at the height of an intensive combat-simulation exposure. We found significantly reduced gene expression levels in resting mononuclear cell nuclear receptor, subfamily 3, member 1 (NR3C1), and its transactivator spindle and kinetochore-associated protein 2 (SKA2), that predict blunted cortisol reactivity to combat-simulation stress among CA exposed adolescents. Long-term alterations in endocrine immune indices, subjective distress, and executive functions persist among healthy high functioning adolescents following milder CA exposure, and may promote resilience or vulnerability to later real-life combat exposure.

Long-term weight control in adults with Prader-Willi syndrome living in residential hostels.

Hyperphagia leading to severe obesity with increased morbidity and mortality is the major manifestation of Prader-Willi syndrome. Caring for these individuals in a home environment is challenging and stressful for caregivers and families. Residential hostels specifically for PWS adults offer programs of diet, exercise, and vocational opportunities, but long-term effects of PWS hostel living have not been reported. We studied long-term changes in body mass index (BMI) for PWS adults living in residential hostels compared with age-matched controls living with families at home. The study included all 34 individuals (18 men) aged >17 years with genetically confirmed PWS living in residential hostels. BMI was recorded at the time of yearly clinic visits and compared to 23 PWS adults (10 men) living at home. BMI on entering the hostel was 36.3 ± 11.0 kg/m2 and decreased to 27.0 ± 5.6 kg/m2 (p < 0.001) after 6.9 ± 3.9 years. For 21 residents, a slight rise of BMI to 28.8 kg/m2 was observed 5.1 ± 2.5 years after the lowest value was achieved. BMI of 23 PWS adults at home was 36.8 ± 12.7 kg/m2 versus 27.9 ± 7.1 kg/m2 for hostel residents in the same age range (p = 0.008). From 2008 to 2019, there were five deaths among PWS individuals aged 18-40 years living at home, compared with one death (a 43-year-old man) among hostel residents. Adults with PWS living in hostels lose weight, maintain BMI values in a normal to mildly overweight range, and have lower mortality in contrast to individuals in a family home environment.

Myokine levels after resistance exercise in young adults with Prader-Willi syndrome (PWS).

Individuals with PWS require marked caloric restriction and daily exercise to prevent morbid obesity. Lower energy expenditure, hypotonia, decreased muscle mass, and cognitive impairment make exercise challenging for this population. Exercise guidelines include resistance training as an important component. Myokine responses to resistance exercise may mediate beneficial metabolic effects. We aimed to determine if young PWS adults can perform a resistance exercise program and to measure myokine responses in PWS versus age- and BMI-matched controls. Each group included 11 participants (7M/4F). Ages and BMI for PWS and controls were 30.7 ± 4.6 versus 30.1 ± 4.3 years and 28.3 ± 4.3 versus 28.2 ± 4.2 kg/m2 , respectively. Glucose, creatine kinase (CK), lactate, and myokines were measured before, after, 30, and 60 min after completing eight resistance exercises. Myokines were assayed using a multiplex myokine panel (Merck Millipore). CK was lower in PWS versus controls (62 ± 16 vs.322 ± 100 U/L, p < .04). Peak lactate was 3.7 ± 0.7 in PWS versus 7.3 ± 0.7 mmol/Lin controls (p < .001). The increase in interleukin-6 was similar in PWS and controls (41 ± 16% and 35 ± 10%, respectively). Pre- and post-exercise levels of the six myokines assayed showed no consistent differences between the PWS and control participants. PWS young adults are capable of performing resistance/strength-building exercise. The lower CK and peak lactate levels in PWS may reflect decreased muscle mass in this population. Further studies are needed to determine optimal exercise regimens and assess the role of myokines incontributing to the metabolic phenotype of PWS.

Risk factors for the development of medical stress syndrome following surgical intervention.

BACKGROUND: Pediatric surgical procedures involve traumatic stress that may cause psychological distress, leading to decreased adherence to continued surgical follow-up and delayed physical recovery. Risk factors for pediatric medical trauma, however, have not been studied enough. We aim to define the risk factors detectable during hospitalization in pediatric surgery and characterize children at risk of developing PTSD, in order to focus preventive interventions on these children. METHODS: The participants in this prospective study were parents of 235 children aged 1-13 years hospitalized in a pediatric surgical ward, who form a representative sample of patients of this age in the ward. They completed questionnaires measuring symptoms of psychological distress, 3-5 months after discharge. RESULTS: Higher parental stress, parental concerns regarding family social support, and parental concerns regarding sibling problems had a significant positive correlation with the children's emotional distress measured 3-5 months after hospitalization. Among children aged 1-5 years, emergency (as opposed to elective) operation and a higher number of invasive procedures were also positively correlated with the children's PTSS. CONCLUSIONS: There is a need to develop measurements for identifying children at high risk for developing posttraumatic stress following surgical intervention; guidelines for developing such a screening instrument are outlined. TYPE OF STUDY: Prognosis study (level of evidence - 1).

Traumatic Stress Among Children After Surgical Intervention for Congenital Melanocytic Nevi: A Pilot Study.

BACKGROUND: Hospitalization and surgery are traumatic experiences that can result after traumatic stress symptoms (PTSS). Surgical interventions for congenital melanocytic nevus (CMN) can be very stressful, but their potential for causing PTSS has not been studied. We aim to determine prospectively whether children undergoing surgery for CMN develop PTSS and what are the specific risk factors for such an event. OBJECTIVE: The authors aim to determine prospectively whether children undergoing surgery for CMN develop PTSS and what the specific risk factors for such an event are. METHODS: Thirty children who were consecutively hospitalized in a pediatric surgery ward for CMN removal during the study period were recruited voluntarily. About 4 months after discharge from the hospital, the children and their parents were assessed for psychological distress. RESULTS: At the assessment 4 months after hospitalization, the children displayed a significant increase in symptoms of distress in comparison with baseline levels. Moreover, 33.3% met full post-traumatic stress disorder (PTSD) diagnostic criteria. The number of invasive procedures, family resources, and parental distress predicted 40% of the variance in PTSS, with parental distress predicting it most significantly. CONCLUSION: The high prevalence of PTSS among children undergoing CMN removal and among their parents emphasizes the importance of actions for prevention and early treatment of psychological distress.

Traumatic Stress among School-Aged Pediatric Surgery Patients and Their Parents.

INTRODUCTION: Since hospitalization can be a traumatic event for children, many of them may suffer from a cluster of chronic psychological and emotional difficulties called Pediatric Medical Traumatic Stress (PMTS). Although PMTS causes considerable functional impairment and psychological distress and may decrease the children's compliance with post-surgical care, awareness of this condition is low and thus not enough effort is made to prevent it. The objective of this study is to assess prospectively the prevalence and characteristics of PMTS in school-age children following hospitalization in a general pediatric surgery ward and in their parents, which has not been documented before. MATERIALS PATIENTS AND METHODS: We recruited parents of 88 children aged 6 to 13 years old, hospitalized in a pediatric surgery ward and which form a representative sample of the children of this age in the ward. Three to five months after discharge from the hospital, the parents completed questionnaires measuring symptoms of psychological distress. RESULTS: About 26.4% of children displayed symptoms of PMTS, and 11.6% of parents suffered from posttraumatic stress disorder following their child's hospitalization. Moreover, we found a medium high positive correlation between the parents' level of distress and that of their child. CONCLUSION: In view of the prevalence of PMTS among school-aged children following surgical intervention, it is necessary to promote increased awareness, preventive interventions, and early identification and treatment of this condition.

Should parents share medical information with their young children? A prospective study.

BACKGROUND: As psychiatric consultants to pediatric wards, we are often asked whether to disclose to young children full information about the invasive medical procedures they face. To date, no studies have been published offering an evidence-based answer to this question. This prospective study examined whether sharing medical information with young children regarding invasive interventions correlates with the development of chronic post-traumatic stress three to five months after hospitalization. METHOD: The participants in this prospective study were parents of 151 children aged 3-13 who were hospitalized in a pediatric surgery ward. The sample was representative of the population hospitalized in this ward during that year. Independent of the study, parents of 104 children chose to share with them information regarding the procedure they were about to undergo, while parents of 47 children chose not to do so. t-Tests were used to assess the correlation between the children's exposure to medical information and their level of long-term post-intervention stress. RESULTS: Findings show an inverse correlation between the children's exposure to medical information and their level of post-traumatic stress several months after their medical episode. The correlation is significant in both preschool children and school-aged children. CONCLUSIONS: We suggest the implementation of psychoeducation programs among both medical staff and parents in order to increase awareness of the importance of sharing medical information with young children facing medical challenges.

Surgical procedures and pediatric medical traumatic stress (PMTS) syndrome: Assessment and future directions.

INTRODUCTION: Surgical procedures involve traumatic stress. Children may develop chronic psychological distress and dysfunction after surgery, with consequent reluctance to comply with medical follow-up care. A literature review of this topic shows that it has been understudied. Our study aims to assess the frequency and characteristics of symptoms of persistent psychological distress in children following surgery, which have not been documented before, in order to promote its awareness and its early identification. METHODS: Parents of 79 children (aged 1-6) that were hospitalized in a pediatric surgical ward, comprising a representative sample, completed three validated questionnaires assessing their children's psychological symptoms 3-5months after the hospitalization. RESULTS: A significant portion of children suffer from psychological distress 3-5months after hospitalization. Moreover, 10.39% of the children exhibited symptoms of PTSD, and 28.6% of parents reported that the child's distress causes dysfunction. Additionally, our findings emphasize the parents' concerns regarding the child's behavior, function, and health following hospitalization. CONCLUSION: Since a significant prevalence of hospitalization-related traumatic stress is documented, the awareness to it has to be improved, in order to reduce its frequency and increase adherence to medical follow-up care. TYPE OF STUDY: Prognosis study. LEVEL OF EVIDENCE: 1.

A disease specific questionnaire for assessing behavior in individuals with Prader-Willi syndrome.

OBJECTIVE: Prader-Willi syndrome (PWS) is a genetic multisystem disorder with various medical, cognitive, behavioral and psychiatric problems. PWS is caused by the lack of expression of paternal genes on chromosome 15q2-q13 due to a deletion (70-75%), uniparental disomy (25-30%) or imprinting center defect (<5%). The common PWS behavioral and psychiatric characteristics are very typical in all ethnicities and were reported worldwide. Still, each individual has a specific profile of these common traits and the severity of his or her symptoms varies over time. Behavioral problems are the most important factor affecting the quality of life of both the individuals and their families. There is a need for a standardized tool to assess the specific behavioral profile of each individual and its present severity, in order to enable physicians to tailor the specific treatment needed and assist in a more accurate clinical follow up. To the best of our knowledge no such a tool has been standardized and published. We developed, based on the literature (mainly Forster and Gourash's paradigm) and our clinical experience, a 37 item disease specific questionnaire, the "PWS Behavioral Questionnaire" (PWSBQ) for assessing behavior in PWS patients. The purpose of the present study was to validate this tool in the entire adolescent and adult PWS population in Israel. METHODS: The PWSBQ focuses on five major domains-abnormal emotional regulation, food-seeking related behavior, lack of flexibility, oppositional behavior and interpersonal problems and lastly body related behaviors. Caregivers of all Hebrew speaking individuals with PWS over the age of 12 years attending the Israeli national multidisciplinary PWS clinic were recruited. Of the 54 eligible individuals, 53 participated. They were interviewed with the PWSBQ and in addition filled the "Hyperphagia Questionnaire" and the "Child Behavioral Checklist" (CBCL). After verifying the questionnaire's content validity, all items on the PWSBQ were analyzed for internal reliability by calculating Cronbach's α. Criterion validity was evaluated by correlation testing with regard to the Hyperphagia Questionnaire and CBCL. In order to assess the questionnaire's interpretability, the correlation between the PWSBQ and the "Clinical Global Impression" (CGI) scores was evaluated. RESULTS: The PWSBQ total score was positively correlated with both the CBCL total score and the CGI score (0.662 and 0.549, p<0.001 respectively). Of the five domains, four had acceptable internal reliability (excluding the body related behaviors domain, which was thus removed from the total score). Criterion validity was established for the four domains remaining in the statistical analysis (abnormal emotional regulation, food seeking related behavior, lack of flexibility and oppositional behavior and interpersonal problems). CONCLUSIONS: Our findings suggest that the PWSBQ is a valid and reliable tool for the assessment of current behavioral problems among individuals with PWS. Although further research is needed in order to verify PWSBQ's ability to identify changes in the behavioral status of a given individual, it can now be used both in research and in a clinical setting, enabling the physician to plan the most suitable treatment based on the current behavioral status.

Cross-disorder genome-wide analyses suggest a complex genetic relationship between Tourette's syndrome and OCD.

OBJECTIVE: Obsessive-compulsive disorder (OCD) and Tourette's syndrome are highly heritable neurodevelopmental disorders that are thought to share genetic risk factors. However, the identification of definitive susceptibility genes for these etiologically complex disorders remains elusive. The authors report a combined genome-wide association study (GWAS) of Tourette's syndrome and OCD. METHOD: The authors conducted a GWAS in 2,723 cases (1,310 with OCD, 834 with Tourette's syndrome, 579 with OCD plus Tourette's syndrome/chronic tics), 5,667 ancestry-matched controls, and 290 OCD parent-child trios. GWAS summary statistics were examined for enrichment of functional variants associated with gene expression levels in brain regions. Polygenic score analyses were conducted to investigate the genetic architecture within and across the two disorders. RESULTS: Although no individual single-nucleotide polymorphisms (SNPs) achieved genome-wide significance, the GWAS signals were enriched for SNPs strongly associated with variations in brain gene expression levels (expression quantitative loci, or eQTLs), suggesting the presence of true functional variants that contribute to risk of these disorders. Polygenic score analyses identified a significant polygenic component for OCD (p=2×10(-4)), predicting 3.2% of the phenotypic variance in an independent data set. In contrast, Tourette's syndrome had a smaller, nonsignificant polygenic component, predicting only 0.6% of the phenotypic variance (p=0.06). No significant polygenic signal was detected across the two disorders, although the sample is likely underpowered to detect a modest shared signal. Furthermore, the OCD polygenic signal was significantly attenuated when cases with both OCD and co-occurring Tourette's syndrome/chronic tics were included in the analysis (p=0.01). CONCLUSIONS: Previous work has shown that Tourette's syndrome and OCD have some degree of shared genetic variation. However, the data from this study suggest that there are also distinct components to the genetic architectures of these two disorders. Furthermore, OCD with co-occurring Tourette's syndrome/chronic tics may have different underlying genetic susceptibility compared with OCD alone.

Copy number variation in obsessive-compulsive disorder and tourette syndrome: a cross-disorder study.

OBJECTIVE: Obsessive-compulsive disorder (OCD) and Tourette syndrome (TS) are heritable neurodevelopmental disorders with a partially shared genetic etiology. This study represents the first genome-wide investigation of large (>500 kb), rare (<1%) copy number variants (CNVs) in OCD and the largest genome-wide CNV analysis in TS to date. METHOD: The primary analyses used a cross-disorder design for 2,699 case patients (1,613 ascertained for OCD, 1,086 ascertained for TS) and 1,789 controls. Parental data facilitated a de novo analysis in 348 OCD trios. RESULTS: Although no global CNV burden was detected in the cross-disorder analysis or in secondary, disease-specific analyses, there was a 3.3-fold increased burden of large deletions previously associated with other neurodevelopmental disorders (p = .09). Half of these neurodevelopmental deletions were located in a single locus, 16p13.11 (5 case patient deletions: 0 control deletions, p = .08 in the current study, p = .025 compared to published controls). Three 16p13.11 deletions were confirmed de novo, providing further support for the etiological significance of this region. The overall OCD de novo rate was 1.4%, which is intermediate between published rates in controls (0.7%) and in individuals with autism or schizophrenia (2-4%). CONCLUSION: Several converging lines of evidence implicate 16p13.11 deletions in OCD, with weaker evidence for a role in TS. The trend toward increased overall neurodevelopmental CNV burden in TS and OCD suggests that deletions previously associated with other neurodevelopmental disorders may also contribute to these phenotypes.

Partitioning the heritability of Tourette syndrome and obsessive compulsive disorder reveals differences in genetic architecture.

The direct estimation of heritability from genome-wide common variant data as implemented in the program Genome-wide Complex Trait Analysis (GCTA) has provided a means to quantify heritability attributable to all interrogated variants. We have quantified the variance in liability to disease explained by all SNPs for two phenotypically-related neurobehavioral disorders, obsessive-compulsive disorder (OCD) and Tourette Syndrome (TS), using GCTA. Our analysis yielded a heritability point estimate of 0.58 (se = 0.09, p = 5.64e-12) for TS, and 0.37 (se = 0.07, p = 1.5e-07) for OCD. In addition, we conducted multiple genomic partitioning analyses to identify genomic elements that concentrate this heritability. We examined genomic architectures of TS and OCD by chromosome, MAF bin, and functional annotations. In addition, we assessed heritability for early onset and adult onset OCD. Among other notable results, we found that SNPs with a minor allele frequency of less than 5% accounted for 21% of the TS heritability and 0% of the OCD heritability. Additionally, we identified a significant contribution to TS and OCD heritability by variants significantly associated with gene expression in two regions of the brain (parietal cortex and cerebellum) for which we had available expression quantitative trait loci (eQTLs). Finally we analyzed the genetic correlation between TS and OCD, revealing a genetic correlation of 0.41 (se = 0.15, p = 0.002). These results are very close to previous heritability estimates for TS and OCD based on twin and family studies, suggesting that very little, if any, heritability is truly missing (i.e., unassayed) from TS and OCD GWAS studies of common variation. The results also indicate that there is some genetic overlap between these two phenotypically-related neuropsychiatric disorders, but suggest that the two disorders have distinct genetic architectures.