Partitioning the Heritability of Tourette Syndrome and Obsessive Compulsive Disorder Reveals Differences in Genetic Architecture

Abstract

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.

Homogeneous case subgroups increase power in genetic association studies

“…This approach showed shared genetic susceptibility to psychiatric disorders 28 and that Tourette syndrome and obsessive-compulsive disorder are genetically distinct. 29 The approach can easily be adapted to interrogate disease subgroups, where a low genetic correlation in a well-powered sample Power of subgroup genetic analyses M Traylor et al would imply distinct genetic architecture. Similarly, genetic risk profile scoring, in which the cumulative effect of genome-wide SNPs is used to test for differences between sets of cases and controls, can be used for the same purpose.…”

Shared genetic contribution to ischemic stroke and Alzheimer's disease

“…These approaches use distant relatedness between individuals to infer heritability and coheritability of complex traits and have been used to provide insights into and between many diseases 35, 36, 37. We performed a bivariate GREML analysis in two large GWAS cohorts consisting of AD and IS cases and controls to assess evidence of a shared genetic contribution to the two diseases.…”

Histaminergic modulation in Tourette syndrome

“…As with other neurodevelopmental conditions, there is solid evidence for a genetic component to the expression of TS [32,33], thought to involve complex multigene changes [34]. TS has a heritability of approximately 0.58 [35] and its genetic heterogeneity has recently been confirmed by the results of recent large studies, which have failed to identify a single shared mutation or even common polymorphisms [36].…”