Christie L. Burton

Revealing the complex genetic architecture of obsessive-compulsive disorder using meta-analysis

Two obsessive–compulsive disorder (OCD) genome-wide association studies (GWASs) have been published by independent OCD consortia, the International Obsessive-Compulsive Disorder Foundation Genetics Collaborative (IOCDF-GC) and the OCD Collaborative Genetics Association Study (OCGAS), but many of the top-ranked signals were supported in only one study. We therefore conducted a meta-analysis from the two consortia, investigating a total of 2688 individuals of European ancestry with OCD and 7037 genomically matched controls. No single-nucleotide polymorphisms (SNPs) reached genome-wide significance. However, in comparison with the two individual GWASs, the distribution of P-values shifted toward significance. The top haplotypic blocks were tagged with rs4733767 (P=7.1 × 10−7; odds ratio (OR)=1.21; confidence interval (CI): 1.12–1.31, CASC8/CASC11), rs1030757 (P=1.1 × 10−6; OR=1.18; CI: 1.10–1.26, GRID2) and rs12504244 (P=1.6 × 10−6; OR=1.18; CI: 1.11–1.27, KIT). Variants located in or near the genes ASB13, RSPO4, DLGAP1, PTPRD, GRIK2, FAIM2 and CDH20, identified in linkage peaks and the original GWASs, were among the top signals. Polygenic risk scores for each individual study predicted case–control status in the other by explaining 0.9% (P=0.003) and 0.3% (P=0.0009) of the phenotypic variance in OCGAS and the European IOCDF-GC target samples, respectively. The common SNP heritability in the combined OCGAS and IOCDF-GC sample was estimated to be 0.28 (s.e.=0.04).xa0Strikingly, ∼65% of the SNP-based heritability in the OCGAS sample was accounted for by SNPs with minor allele frequencies of ⩾40%. This joint analysis constituting the largest single OCD genome-wide study to date represents a major integrative step in elucidating the genetic causes of OCD.

Uncovering obsessive-compulsive disorder risk genes in a pediatric cohort by high-resolution analysis of copy number variation.

BackgroundObsessive-compulsive disorder (OCD) is a heterogeneous neuropsychiatric condition, thought to have a significant genetic component. When onset occurs in childhood, affected individuals generally exhibit different characteristics from adult-onset OCD, including higher prevalence in males and increased heritability. Since neuropsychiatric conditions are associated with copy number variations (CNVs), we considered their potential role in the etiology of OCD.MethodsWe genotyped 307 unrelated pediatric probands with idiopathic OCD (including 174 that were part of complete parent-child trios) and compared their genotypes with those of 3861 population controls, to identify rare CNVs (<0.5xa0% frequency) of at least 15xa0kb in size that might contribute to OCD.ResultsWe uncovered de novo CNVs in 4/174 probands (2.3xa0%). Our case cohort was enriched for CNVs in genes that encode targets of the fragile X mental retardation protein (nominal pu2009=u20091.85u2009×u200910−03; FDR=0.09), similar to previous findings in autism and schizophrenia. These results also identified deletions or duplications of exons in genes involved in neuronal migration (ASTN2), synapse formation (NLGN1 and PTPRD), and postsynaptic scaffolding (DLGAP1 and DLGAP2), which may be relevant to the pathogenesis of OCD. Four cases had CNVs involving known genomic disorder loci (1q21.1-21.2, 15q11.2-q13.1, 16p13.11, and 17p12). Further, we identified BTBD9 as a candidate gene for OCD. We also sequenced exomes of ten “CNV positive” trios and identified in one an additional plausibly relevant mutation: a 13xa0bp exonic deletion in DRD4.ConclusionsOur findings suggest that rare CNVs may contribute to the etiology of OCD.

A Review of the Role of Serotonin System Genes in Obsessive-Compulsive Disorder

HIGHLIGHTSReview obsessive‐compulsive disorder and the role of serotonin system genes.Summarize candidate serotonin system gene studies conducted and suggest reasons for inconclusive findings.Help direct future genetic studies given our understanding of genetic complexity and phenotypic heterogeneity in OCD. ABSTRACT Obsessive‐compulsive disorder (OCD) is a debilitating neuropsychiatric disorder that causes the patient to experience intrusive thoughts and/or to carry out repetitive, ritualized behaviors that are time consuming and impairing. OCD is familial and heritable. The genetic factors responsible for pathogenesis, however, remain largely unknown despite the numerous candidate gene studies conducted. Based on efficacy of serotonin reuptake inhibitors (SRIs) in treating OCD, serotonin system genes have been a dominant focus in OCD candidate gene studies. We review the most commonly studied candidate serotonin system gene variants (specifically in SLC6A4, HTR2A, HTR1B, and HTR2C) and their association with OCD. Although findings to date are mixed, serotonin transporter polymorphism 5‐HTTLPR and HTR2A polymorphism rs6311 (or rs6313) are most consistently associated with OCD. Mixed findings may be the result of genetic complexity and phenotypic heterogeneity that future studies should account for. Homogenous patient subgroups reflecting OCD symptom dimensions, OCD subtypes, and sex should be used for gene discovery.

The Toronto Obsessive-Compulsive Scale: Psychometrics of a Dimensional Measure of Obsessive-Compulsive Traits

OBJECTIVEnTo describe the Toronto Obsessive-Compulsive Scale (TOCS), a novel 21-item parent- or self-report questionnaire that covers wide variation in obsessive-compulsive (OC) traits, and to evaluate its psychometric properties in a community-based pediatric sample.nnnMETHODnThe TOCS was completed for 16,718 children and adolescents between the ages of 6 and 17 years in axa0community setting. Internal consistency, convergent validity with the Obsessive-Compulsive Scale of the Child Behaviour Checklist (CBCL-OCS), divergent validity with the Strengths and Weaknesses of ADHD (Attention-Deficit/Hyperactivity Disorder) Symptoms and Normal Behaviour Rating Scale (SWAN), interrater reliability, as well as sensitivity and specificity of the TOCS were assessed.nnnRESULTSnThe internal consistency of the 21 TOCS items was excellent (Cronbachs αxa0= 0.94). TOCS was moderately correlated with the CBCL-OCS (Spearman correlationxa0= 0.51) and poorly correlated with the SWAN (Pearson correlationxa0= 0.02). Sensitivity and specificity analyses indicated that a TOCS total score of greater than 0 successfully discriminated community-reported obsessive-compulsive disorder (OCD) cases from noncases. OC traits were continuously distributed both at the total score and dimensional level in our pediatric community sample.nnnCONCLUSIONnTOCS is a multidimensional measure of OCxa0traits in children and adolescents with sound psychometric properties. TOCS reveals that OC traits are common and continuously distributed in a community sample. TOCS may be a useful measure for studies of the characteristics and etiology of OC traits.

Clinical Correlates of Hoarding With and Without Comorbid Obsessive-Compulsive Symptoms in a Community Pediatric Sample

OBJECTIVEnWe assessed the prevalence and clinical correlates of hoarding, with and without obsessive-compulsive (OC) symptoms, in a community-based pediatric sample.nnnMETHODnWe measured hoarding and OC symptoms using the Toronto Obsessive-Compulsive Scale (TOCS) in 16,718 youth aged 6 to 17 years in the community. We classified participants with high and low symptom counts for hoarding and OC into 4 groups: hoarding+OC; hoarding-only; OC-only; and control (no OC or hoarding symptoms). We compared these 4 groups on parent- or self-reported medical and psychiatric conditions, anxiety symptoms measured with the Child Behavior Checklist (CBCL), and attention-deficit/hyperactivity disorder (ADHD) symptoms measured with the Strengths and Weaknesses of Attention-Deficit/Hyperactivity Disorder Symptoms and Normal Behavior Scale (SWAN).nnnRESULTSnAlmost 10% of participants were in the high hoarding group. Of these participants, 40% did not fall into the high OC group. The prevalence of reported psychiatric disorders (e.g., ADHD, autism spectrum disorder, obsessive-compulsive disorder) was greater in the hoarding (hoarding+OC and hoarding-only) and OC groups (hoarding+OC and OC-only) than in the nonhoarding (OC-only and control) and non-OC groups (hoarding-only and control), respectively. ADHD, specifically inattentive, symptoms were more common in the hoarding-only than in the OC-only group while anxiety symptoms were more common in the OC-only than in the hoarding-only group.nnnCONCLUSIONnIn a community pediatric sample, hoarding symptoms occurred in both the presence and absence of obsessive-compulsive symptoms. Hoarding symptoms alone had some unique clinical correlates, in particular, more inattentive ADHD symptoms and fewer anxiety symptoms. These findings suggest that hoarding is distinct from OC traits in youth.

Summaries of oral sessions at the XXI World Congress of Psychiatric Genetics, Boston, Massachusetts, 17-21 October 2013: state of the field

The XXI World Congress of Psychiatric Genetics (WCPG), sponsored by the International Society of Psychiatric Genetics (ISPG), took place in Boston, Massachusetts, on 17–21 October 2013. Approximately 900 participants gathered to discuss the latest findings in this rapidly advancing field. The following report was written by student travel awardees. Each was assigned one or more sessions as a rapporteur. This manuscript represents topics covered in most, but not all of the oral presentations during the conference, and contains some of the major notable new findings reported.

Utility of Attention-Deficit/Hyperactivity Disorder Trait Measure in Population Genetics: A Polygenic Risk Study

Background Valid and genetically-informative trait measures of psychopathology collected in the general population would provide a powerful complement to case/control genetic designs. We report the convergent, predictive and discriminant validity of the parent- and the self-report versions of the Strengths and Weaknesses of ADHD Symptoms and Normal Behavior Rating Scale (SWAN) for attention-deficit/hyperactivity disorder (ADHD) traits. We tested if SWAN ADHD scores were associated with ADHD diagnosis, ADHD polygenic risk, as well as with traits and polygenic risk for co-occurring disorders such as anxiety and obsessive-compulsive disorder (OCD). Methods We collected parent- and self-report SWAN scores in a community sample (n=15,560; 6-18 years of age) and created norms. Sensitivity-specificity analyses determined SWAN cut-points that discriminated those with a community ADHD diagnosis (n=972) from those without a community diagnosis. We validated cut-points from the community sample in a clinical sample (266 ADHD cases; 36 controls). We tested if SWAN scores were associated with anxiety and obsessive-compulsive (OC) traits and polygenic risk for ADHD, OCD and anxiety disorders. Results Both the parent- and the self-report SWAN measures showed high convergent validity with established ADHD measures and distinguished ADHD participants with high sensitivity and specificity in the community sample. Cut-points established in the community sample discriminated ADHD clinic cases from controls with a sensitivity of 86% and specificity of 94%. High parent- and self-report SWAN scores and scores above the community-based cut-points were associated with polygenic risk for ADHD. High ADHD traits were associated with high anxiety traits, but not OC traits. SWAN scores were not associated with OCD or anxiety disorder polygenic risk. Conclusion The parent- and self-report SWAN are potentially useful in genetic research because they predict ADHD diagnoses and are associated with ADHD polygenic risk.Background: We tested the utility of the SWAN (Strengths and Weaknesses of ADHD Symptoms and Normal Behavior Rating Scale) for measuring attention-deficit/hyperactivity disorder (ADHD) traits in population-based genetics. We examined the convergent, predictive, and discriminant validity of the SWAN parent- and new youth report scale while creating norms and clinical cut-offs. We tested if high ADHD traits were associated with ADHD diagnosis and polygenic risk and if low ADHD traits pointed to another psychopathological phenotype or genetic risk.nMethods: We collected parent- and youth-reported SWAN scores in a community sample (n=15,560; 6-18 years of age). Sensitivity-specificity analyses determined SWAN scores that discriminated a community ADHD diagnosis (n=972). Cut-offs were validated in a clinic sample (266 ADHD patients; 36 controls). We examined the relationship of SWAN scores with anxiety, obsessive-compulsive (OC) traits as well as ADHD, obsessive-compulsive disorder (OCD), and anxiety disorder using polygenic risk scores.nResults: SWAN scores showed high convergent validity and distinguished ADHD participants with high sensitivity and specificity in the community sample. The community-based threshold discriminated ADHD clinic cases from controls with a sensitivity of 86% and specificity of 94%. High ADHD traits were associated with high anxiety, but not OC, traits. High SWAN scores and those above the community-based cut-off were only associated with ADHD polygenic risk.nConclusions: The SWAN is useful for genetic research because it predicts ADHD diagnoses with high sensitivity and specificity and is associated with ADHD polygenic risk. Cut-off values and norms are presented. Low ADHD traits were not associated with other psychopathology.

Factor Structure and Heritability of Obsessive-Compulsive Traits in Children and Adolescents in the General Population

Background Obsessive-compulsive disorder (OCD) is a heritable childhood-onset psychiatric disorder that may represent the extreme of obsessive-compulsive (OC) traits that are widespread in the general population. We studied the factor structure and heritability of the Toronto Obsessive Compulsive Scale (TOCS), a new measure designed to assess traits associated with OCD in children and adolescents. We also examined the degree to which genetic effects are unique and shared between dimensions. Methods OC traits were measured using the TOCS in 16,718 children and adolescents (6 to 18 years) at a local science museum. Factor analysis was conducted to identify OC trait dimensions. Univariate and multivariate twin modeling was performed to estimate the heritability of OC trait dimensions in a subset of twins (220 pairs). Results Six OC dimensions were identified: Cleaning/Contamination, Hoarding, Rumination, Superstition, Counting/Checking, and Symmetry/Ordering. The TOCS total score (74%) and OC trait dimensions were heritable (30-77%). Hoarding was phenotypically distinct but shared genetic effects with other OC dimensions. Most of the genetic effects were shared between dimensions while unique environment accounted for the majority of dimension-specific variance, except for hoarding which had considerable unique genetic factors. A latent trait did not account for the shared variance between dimensions. Conclusions OC traits and individual OC dimensions were heritable, although the degree of shared and dimension-specific etiological factors varied by dimension. The TOCS is useful for genetic research of OC traits and OC dimensions should be examined individually and together along with total trait scores to characterize OC genetic architecture.

Heritability of obsessive–compulsive trait dimensions in youth from the general population

Obsessive–compulsive disorder (OCD) is a heritable childhood-onset psychiatric disorder that may represent the extreme of obsessive–compulsive (OC) traits that are widespread in the general population. We report the heritability of the Toronto Obsessive–Compulsive Scale (TOCS), a new measure designed to assess the complete range of OC traits in youth. We also examined the dimensional nature of the TOCS and the degree to which genetic effects are unique or shared between dimensions. OC traits were measured using the TOCS in 16,718 youth (6–18 years) at a science museum. We conducted a factor analysis to identify OC trait dimensions. We used univariate and multivariate twin models to estimate the heritability of OC trait dimensions in a subset of twins (220 pairs). Six OC dimensions were identified: Cleaning/Contamination, Symmetry/Ordering, Rumination, Superstition, Counting/Checking, and Hoarding. The TOCS total score (74%) and each OC dimension was heritable (30–77%). Hoarding was not highly correlated with other OC dimensions, but did share genetic effects. Shared genetics accounted for most of the shared variance among dimensions, whereas unique environment accounted for the majority of dimension-specific variance. One exception was Hoarding, which had considerable unique genetic factors. A latent trait did not account for the shared variance between dimensions. In conclusion, OC traits and individual OC dimensions were heritable, although the degree of shared and dimension-specific etiological factors varied by dimension. The TOCS may be informative for genetic research of OC traits in youth. Genetic research of OC traits should consider both OC dimension and total trait scores.

Examination of the shared genetic basis of anorexia nervosa and obsessive–compulsive disorder

Anorexia nervosa (AN) and obsessive–compulsive disorder (OCD) are often comorbid and likely to share genetic risk factors. Hence, we examine their shared genetic background using a cross-disorder GWAS meta-analysis of 3495 AN cases, 2688 OCD cases, and 18,013 controls. We confirmed a high genetic correlation between AN and OCD (rgu2009=u20090.49u2009±u20090.13, pu2009=u20099.07u2009×u200910−7) and a sizable SNP heritability (SNP h2u2009=u20090.21u2009±u20090.02) for the cross-disorder phenotype. Although no individual loci reached genome-wide significance, the cross-disorder phenotype showed strong positive genetic correlations with other psychiatric phenotypes (e.g., rgu2009=u20090.36 with bipolar disorder and 0.34 with neuroticism) and negative genetic correlations with metabolic phenotypes (e.g., rgu2009=u2009−0.25 with body mass index and −0.20 with triglycerides). Follow-up analyses revealed that although AN and OCD overlap heavily in their shared risk with other psychiatric phenotypes, the relationship with metabolic and anthropometric traits is markedly stronger for AN than for OCD. We further tested whether shared genetic risk for AN/OCD was associated with particular tissue or cell-type gene expression patterns and found that the basal ganglia and medium spiny neurons were most enriched for AN–OCD risk, consistent with neurobiological findings for both disorders. Our results confirm and extend genetic epidemiological findings of shared risk between AN and OCD and suggest that larger GWASs are warranted.