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

Baseline Anxiety and Depression and Risk for ICU Delirium: A Prospective Cohort Study

OBJECTIVES: Anxiety and depression are common mental disorders in adults admitted to the ICU. Although depression increases postsurgical delirium and anxiety does not, their associations with ICU delirium in critically ill adults remain unclear. We evaluated the association between ICU baseline anxiety and depression and ICU delirium occurrence. DESIGN: Subgroup analysis of a prospective cohort study. SETTING: Single, 36-bed mixed ICU. PATIENTS: Nine-hundred ninety-one ICU patients admitted with or without delirium between July 2016 and February 2020; patients admitted after elective surgery or not assessed for anxiety/depression were excluded. INTERVENTION: None. MEASUREMENTS AND MAIN RESULTS: The Hospital Anxiety and Depression Scale questionnaire was administered at ICU admission to determine baseline anxiety and depression. All patients were assessed with the Confusion Assessment Method for the ICU (CAM-ICU) q8h; greater than or equal to 1 +CAM-ICU assessment and/or scheduled antipsychotic use represented a delirium day. Multivariable logistic and Quasi-Poisson regression models, adjusted for ICU days and nine delirium risk variables ("Pre-ICU": age, Charlson Comorbidity Index, cognitive impairment; "ICU baseline": Acute Physiology and Chronic Health Evaluation-IV, admission type; "Daily ICU": opioid and/or benzodiazepine use, Sequential Organ Failure Assessment score, coma), were used to evaluate associations between baseline anxiety and/or depression and ICU delirium. Among the 991 patients, 145 (14.6%) had both anxiety and depression, 78 (7.9%) had anxiety only, 91 (9.2%) had depression only, and 677 (68.3%) had neither. Delirium occurred in 406 of 991 total cohort (41.0%) patients; in the baseline anxiety and depression group, it occurred in 78 of 145 (53.8%), in the anxiety only group, 37 of 78 (47.4%), in the depression only group, 39 of 91 (42.9%), and in the group with neither in 252 of 677 (37.2%). Presence of both baseline anxiety and depression was associated with greater delirium occurrence (adjusted odds ratio, 1.99; 95% CI, 1.10-3.53; p = 0.02) and duration (adjusted risk ratio, 1.62; 95% CI, 1.17-2.23; p < 0.01). CONCLUSIONS: Baseline anxiety and depression are associated with increased ICU delirium occurrence and should be considered when delirium risk reduction strategies are being formulated

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 identi fication 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 aGWAS 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 signi ficance, 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=2x1

Cross-Disorder Genome-Wide Analyses Suggest a Complex Genetic Relationship Between Tourette&apos;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=2 710(-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