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

Genome-wide association study of Tourette Syndrome

Tourette Syndrome (TS) is a developmental disorder that has one of the highest familial recurrence rates among neuropsychiatric diseases with complex inheritance. However, the identification of definitive TS susceptibility genes remains elusive. Here, we report the first genome-wide association study (GWAS) of TS in 1285 cases and 4964 ancestry-matched controls of European ancestry, including two European-derived population isolates, Ashkenazi Jews from North America and Israel, and French Canadians from Quebec, Canada. In a primary meta-analysis of GWAS data from these European ancestry samples, no markers achieved a genome-wide threshold of significance (p<5 × 10−8); the top signal was found in rs7868992 on chromosome 9q32 within COL27A1 (p=1.85 × 10−6). A secondary analysis including an additional 211 cases and 285 controls from two closely-related Latin-American population isolates from the Central Valley of Costa Rica and Antioquia, Colombia also identified rs7868992 as the top signal (p=3.6 × 10−7 for the combined sample of 1496 cases and 5249 controls following imputation with 1000 Genomes data). This study lays the groundwork for the eventual identification of common TS susceptibility variants in larger cohorts and helps to provide a more complete understanding of the full genetic architecture of this disorder

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

The Impact of Parents’ Subjective Preparedness on Their Children’s Post-Traumatic Symptoms Following Surgery

The role of parental factors in the emergence of post-traumatic stress symptoms (PTSSs) following pediatric surgeries is well recognized, but the specific influence of parents’ subjective preparedness for their child’s surgery has not been explored. In a study involving 253 children hospitalized in a pediatric surgery ward, parents completed a demographic questionnaire during their child’s stay, which included the question, “As a parent, have you been prepared for the surgical intervention your child is undergoing?” Four months post-surgery, the same parents were interviewed using two questionnaires that evaluated their children’s post-traumatic symptoms. Our findings indicate that in emergency surgical settings, children whose parents felt prepared experienced significantly fewer PTSSs compared to children whose parents did not feel prepared. In contrast, for elective surgeries, parental subjective perception of preparedness did not significantly impact the children’s PTSSs. We conclude that for emergency surgical procedures, addressing parents’ subjective preparedness could be crucial. Further research is necessary to develop targeted interventions that leverage this insight to minimize the risk of PTSSs in children undergoing emergency surgeries

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

The FSH-inhibin axis in prader-willi syndrome: heterogeneity of gonadal dysfunction

Abstract Background We characterized the spectrum and etiology of hypogonadism in a cohort of Prader-Willi syndrome (PWS) adolescents and adults. Methods Reproductive hormonal profiles and physical examination were performed on 19 males and 16 females ages 16–34 years with PWS. Gonadotropins, sex-steroids, inhibin B (INB) and anti-Mullerian hormone (AMH) were measured. We defined 4 groups according to the relative contribution of central and gonadal dysfunction based on FSH and INB levels: Group A: primary hypogonadism (FSH >15 IU/l and undetectable INB (20 pg/ml); Group D: mild central and severe gonadal dysfunction (FSH 1.5–15 IU/l, INB  Results There were 10, 8, 9 and 8 individuals in Groups A-D respectively; significantly more males in group A (9, 4, 4 and 2; P = 0.04). Significant differences between the groups were found in mean testosterone (P = 0.04), AMH (P = 0.003) and pubic hair (P = 0.04) in males and mean LH (P = 0.003) and breast development (P = 0.04) in females. Mean age, height, weight, BMI and the distribution of genetic subtypes were similar within the groups. Conclusions Analysis of FSH and inhibin B revealed four distinct phenotypes ranging from primary gonadal to central hypogonadism. Primary gonadal dysfunction was common, while severe gonadotropin deficiency was rare. Longitudinal studies are needed to verify whether the individual phenotypes are consistent.</p