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

Characterization of SLITRK1 Variation in Obsessive- Compulsive Disorder

Obsessive compulsive disorder (OCD) is a syndrome characterized by recurrent and intrusive thoughts and ritualistic behaviors or mental acts that a person feels compelled to perform. Twin studies, family studies, and segregation analyses provide compelling evidence that OCD has a strong genetic component. The SLITRK1 gene encodes a developmentally regulated stimulator of neurite outgrowth and previous studies have implicated rare variants in this gene in disorders in th

<i>SLITRK1</i> variant N400I fails to induce neurite outgrowth.

<p>(<b>a</b>) LS: Representative images of primary rat E18 hippocampal neurons nucleofected with wildtype <i>SLITRK1</i> or the <i>SLITRK1</i>–N400I variant. RS: Images are also traced to facilitate visualization of thin neurites. Scale bar = 50 µm (<b>b</b>) LS: Representative images of primary mouse E17 cortical neurons nucleofected with wildtype <i>SLITRK1</i> or the <i>SLITRK1</i>–N400I variant. RS: Representative E17 cortical neuron trace. Scale bar = 50 µm (<b>c</b>) The summed total neurite length per hippocampal neuron at 7 <i>div</i> is shown. Each bar on the bar graph represents pooled data of at least 50 neurons per experiment (<i>n</i> = 3). Images are uniformly overexposed to improve neurite visibility. (<b>d</b>) The summed total neurite length per cortical neuron at 3 <i>div</i> is shown. Each bar on the bar graph represents pooled data of at least 14–22 neurons per experiment (<i>n</i> = 2). Statistical significance was assessed using a student's t-test as described under <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0070376#s4" target="_blank">Materials and Methods</a>. Error bars are 95% confidence intervals. * <i>p</i><0.05, ** <i>p</i><0.01, *** <i>p</i><0.001.</p

Novel mutations identified in <i>SLITRK1</i>.

<p>(<b>a</b>) Allelic frequency of novel <i>SLITRK1</i> mutations identified in obsessive-compulsive disorder (OCD) cases. (<b>b</b>) The <i>SLITRK1</i> L63L mutation has been demonstrated by sequencing in one of 762 OC spectrum alleles and in zero of 712 control alleles. (<b>c</b>) The <i>SLITRK1</i> N400I mutation has been demonstrated via sequencing and genotyping in one of 646 OC spectrum alleles and in zero of 2070 control alleles, respectively; <i>^t</i>includes genotyping of 1358 alleles. (<b>d</b>) The <i>SLITRK1</i> T418S mutation has been demonstrated by sequencing in three of 762 OC spectrum alleles and in one of 410 control alleles. (<b>d</b>) Conservation map of <i>SLITRK1</i> region where the three novel mutations were identified (Green – novel variants, gray – evolutionarily conserved regions). (<b>e</b>) A schematic of the <i>SLITRK1</i> protein with the detected variants identified (red – novel variants, gray – previously published variants in Tourette syndrome⁴, black – published variants in trichotillomania⁵. Dotted outline depicts leucine rich repeat (LRR) region 9. Diagram of <i>SLITRK1</i> is available at <a href="http://smart.embl-heidelberg.de" target="_blank">http://smart.embl-heidelberg.de</a>. LRR typ – LRR typical subfamily, LRR CT – LRR C-terminal domain, LRR N-terminal domain; dark blue bar – transmembrane domain.</p

Pedigree diagrams of families with <i>SLITRK1</i> variants.

<p>Pedigrees for individuals in whom <i>SLITRK1</i> variants were identified. Each obsessive-compulsive (OC) spectrum proband is labeled with his/her identifier and is designated by a black arrowhead. Individuals affected with an OC spectrum disorder are represented by shaded symbols, with red shading indicating obsessive-compulsive disorder (OCD) and blue shading indicating Tourette syndrome (TS). Psychiatric conditions outside of the OC spectrum are represented by a magenta circle in the center of the symbol. Male family members are represented with squares, females with circles, persons with unspecified gender are diamonds with the number of individuals indicated directly below. All psychiatric pathology is listed under each affected individual. OCD – Obsessive-Compulsive Disorder, TS – Tourette syndrome, BDD – Body Dysmorphic Disorder, GAD – Generalized Anxiety Disorder, MDD – Major Depressive Disorder, N.O.S. – not otherwise specified, PD – Panic Disorder, PTSD – Post-Traumatic Stress Disorder, w/ - with, y/o – years old, ? – psychiatric history is unavailable for the individual.</p

The Relationship Between Polygenic Risk Scores and Cognition in Schizophrenia

Background Cognitive impairment is a clinically important feature of schizophrenia. Polygenic risk score (PRS) methods have demonstrated genetic overlap between schizophrenia, bipolar disorder (BD), major depressive disorder (MDD), educational attainment (EA), and IQ, but very few studies have examined associations between these PRS and cognitive phenotypes within schizophrenia cases. Methods We combined genetic and cognitive data in 3034 schizophrenia cases from 11 samples using the general intelligence factor g as the primary measure of cognition. We used linear regression to examine the association between cognition and PRS for EA, IQ, schizophrenia, BD, and MDD. The results were then meta-analyzed across all samples. A genome-wide association studies (GWAS) of cognition was conducted in schizophrenia cases. Results PRS for both population IQ (P = 4.39 × 10–28) and EA (P = 1.27 × 10–26) were positively correlated with cognition in those with schizophrenia. In contrast, there was no association between cognition in schizophrenia cases and PRS for schizophrenia (P = .39), BD (P = .51), or MDD (P = .49). No individual variant approached genome-wide significance in the GWAS. Conclusions Cognition in schizophrenia cases is more strongly associated with PRS that index cognitive traits in the general population than PRS for neuropsychiatric disorders. This suggests the mechanisms of cognitive variation within schizophrenia are at least partly independent from those that predispose to schizophrenia diagnosis itself. Our findings indicate that this cognitive variation arises at least in part due to genetic factors shared with cognitive performance in populations and is not solely due to illness or treatment-related factors, although our findings are consistent with important contributions from these factors

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

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

ObjectiveObsessive-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.MethodThe 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.ResultsAlthough 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).ConclusionsPrevious 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