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Cross-Disorder Genome-Wide Analyses Suggest a Complex Genetic Relationship Between Tourette’s Syndrome and OCD

Published Online:1 Jan 2015https://doi.org/10.1176/appi.ajp.2014.13101306

Abstract

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=2×10−4), 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).

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.

Obsessive-compulsive disorder (OCD) [MIM 164230] and Tourette’s syndrome [MIM 137580] are highly familial neuropsychiatric disorders with complex overlapping genetic etiologies (1–3). Some 20%–60% of individuals with Tourette’s syndrome have co-occurring OCD, and 10%–20% of patients initially diagnosed with OCD have Tourette’s syndrome or chronic tics, rates well over what is expected based on their respective population prevalences (4–6). Both disorders are characterized by the presence of repetitive, ritualized, or stereotyped behaviors (tics and compulsions), often preceded by cognitive or sensory phenomena (premonitory urges and obsessions), and clinical differentiation of compulsions versus complex tics can be challenging (7). Genetic epidemiological studies suggest up to 90% shared genetic variance between Tourette’s syndrome/chronic tics and OCD (8–10), and abnormalities in cortico-striatal-thalamo-cortical circuitry have been identified in both conditions (1).

To date, most of the work aimed at elucidating the genetic causes of Tourette’s syndrome and OCD has focused on candidate gene studies and linkage analyses; a few studies examining chromosome abnormalities and copy number variants have also been reported (11–14). Recently, our group performed genome-wide association studies (GWAS) of Tourette’s syndrome and OCD, and for each disorder identified a number of genes and genomic regions of interest, most with modest significance levels. Here we report GWAS results for a combined sample of individuals with Tourette’s syndrome, OCD, or Tourette’s syndrome plus OCD, along with analyses aimed at elucidating the genetic architectures and genetic relationships between the two disorders. Combining these heterogeneous but related phenotypes in joint analyses could have one of two potential effects: 1) enhancement of the genetic signal as a consequence of increased power by adding samples from genetically related phenotypes; or 2) reduction of the genetic signal as a consequence of increased genetic heterogeneity, outweighing the potential benefits of increased sample size. Either way, given previous evidence supporting shared genetic factors and the lack of definitive susceptibility genes for either disorder, joint analyses of Tourette’s syndrome and OCD cases represent an important step toward understanding the underlying causes of these common neuropsychiatric disorders.

Method

Cases

Individuals with Tourette’s syndrome or OCD were recruited as part of collaborative efforts to conduct the first GWAS for these disorders (for details, see references 15, 16). Although data were collected independently for Tourette’s syndrome and OCD, all genotyping and data cleaning were done together, facilitating joint analyses. Participants who were age 18 or older provided written, voluntary informed consent; those under age 18 provided assent, and written parental consent for their participation was obtained. The study was approved by the ethics committees of all participating sites and was in accordance with the Declaration of Helsinki. For the cross-disorder analyses, any participant with either Tourette’s syndrome or OCD was considered affected. For details on the inclusion and exclusion criteria and assessment protocols, see the Supplementary Methods section in the data supplement that accompanies the online edition of this article.

Tourette’s syndrome.

The Tourette’s syndrome sample consisted of 1,286 individuals recruited from 20 sites in the United States, Canada, the United Kingdom, the Netherlands, and Israel, and included individuals of general European (EU) ancestry as well as two EU-derived population isolates of Ashkenazi Jewish (AJ) and French Canadian (FC) descent. Co-occurring OCD symptoms were assessed in 77% of participants; 46% of those evaluated had co-occurring OCD (N=452). OCD status was unknown for 300 individuals with Tourette’s syndrome.

OCD.

The OCD sample consisted of 1,437 individuals with OCD and 290 parent-child trios. While the original GWAS sample consisted of 1,865 OCD probands recruited from 21 sites in North, Central, and South America, Europe, the United Arab Emirates, and South Africa, only individuals of European ancestry (EU, AJ, and EU-derived Afrikaner [SA] descent) were included in the present study (16). Co-occurring Tourette’s syndrome or chronic tics was assessed in 77% of OCD probands; of these, 12% had comorbid Tourette’s syndrome or chronic tics (N=159). Tourette’s syndrome/chronic tics status was unknown for 405 OCD-affected individuals.

Controls

The EU control sample consisted of 4,975 European Caucasian controls primarily derived from cohorts of previously genotyped, unselected population controls (see Supplementary Methods in the online data supplement). Ancestry-matched controls for the FC (N=196) and SA (N=158) samples were collected in parallel with their respective cases (15, 16). Ancestry-matched controls for individuals with AJ ancestry were identified from the EU control sample based on self-reported ancestry and principal-components analysis (N=338).

Genotyping and Quality Control

Genotyping and quality control procedures have been described previously (15, 16; see also Supplementary Methods in the online data supplement). Briefly, case subjects and trios with Tourette’s syndrome or OCD and controls were randomized across plates and genotyped on the Illumina HumanHap610 SNP array (Illumina, San Diego) at the Broad Institute of Harvard-MIT (Cambridge, Mass.) or on the Illumina HumanHap370 at the Yale Center for Genome Analysis (New Haven, Conn.) (see Figure S1 in the online data supplement). Eighty-eight samples were genotyped on both platforms to allow for cross-platform concordance checks. Quality control analyses were performed using PLINK, version 1.07 (17) and EIGENSTRAT (18). Multidimensional scaling analysis was used to exclude case-control samples of non-European descent. Remaining EU and European-derived isolate samples were separated into four strata (EU, AJ, FC, and SA) based initially on self-reported ancestry and then on observed genetic ancestry (15, 16). Imputation was performed with 1000 Genomes Project data (June 2011 Data Release) (19) as the reference panel, using IMPUTE version 2.1.2 (20) (see Supplementary Methods).

Genome-Wide Association Analyses

Individual ancestry-stratified case-control genome-wide association analyses (EU, AJ, FC, and SA) and one case/pseudo-control analysis using the OCD trios were performed in PLINK using logistic regression under an additive model with significant subpopulation-specific multidimensional scaling axes included as covariates to control for residual population stratification (see Figure S2 in the online data supplement). These population-specific analyses were then combined in a fixed-effects model meta-analysis using case-weighting in METAL (21). Single-nucleotide polymorphisms (SNPs) with p values <10−5 were annotated with details including their genomic region and location, allele frequencies, nearby genes, and p values from individual Tourette’s syndrome and OCD GWAS studies. Heterogeneity tests were also conducted to assess subpopulation differences using Cochran’s Q and I2 statistics. As is standard in GWAS for complex traits, a genome-wide threshold of p<5×10−8 was considered statistically significant evidence of association (22, 23).

Enrichment Analyses

GWAS results were examined for enrichment of functional SNPs previously associated with gene expression levels in several brain regions (i.e., expression quantitative trait locus SNPs, eQTLs) or with variation in gene methylation levels (methylation QTLs, mQTLs). eQTL data were generated from cerebellum, parietal cortex, and frontal cortex (see Supplementary Methods in the online data supplement). mQTLs were derived from adult cerebellum (24). Only GWAS SNPs meeting high stringency criteria for eQTLs or mQTLs (p<10−6) were considered. For each phenotype (Tourette’s syndrome, OCD, combined), a quantile-quantile (Q-Q) plot of GWAS disease association p values was generated for eQTL and mQTL SNPs and compared with a standard Q-Q plot of GWAS p values expected under the null distribution assuming no enrichment. A leftward shift in the eQTL/mQTL Q-Q plot relative to the diagonal line (representing the null distribution) indicates enrichment of eQTLs/mQTLs. The level of enrichment of eQTLs or mQTLs in each brain tissue associated with Tourette’s syndrome or OCD was then quantified using a false discovery rate of <0.25, that is, 75% of observed SNPs represent true disease associations (see Supplementary Methods).

Polygenic Score Analysis

Polygenic score analyses were conducted in PLINK using genotyped SNPs to test the hypothesis that multiple genes of small effect jointly contribute to Tourette’s syndrome and OCD susceptibility and to explore the genetic relationships between these disorders (25). Samples were divided into nonoverlapping discovery and target samples (see Supplementary Methods in the online data supplement). For the primary OCD polygenic analysis, cases were restricted to subjects without known co-occurring Tourette’s syndrome/chronic tics. SNPs with GWAS p values passing predetermined significance thresholds (p<0.01, 0.1, 0.2, 0.3, 0.4, and 0.5) in the discovery sample were extracted along with their risk alleles and odds ratios, and then linkage disequilibrium (LD) pruned (r2<0.5). For each significance threshold, a quantitative aggregate risk score was calculated for each individual in the target sample, defined as the sum of the number of risk alleles present at each locus weighted by the log of the odds ratio for that locus estimated from the discovery sample. The relationship between aggregate risk score and case-control status in the target sample was examined at each significance threshold using logistic regression. The percentage of phenotypic variance explained by the aggregate risk score (Nagelkerke’s pseudo-R2) was estimated.

Two separate statistical approaches were used to determine the significance of the observed differences in polygenic risk score prediction between discovery samples. First, permutation testing was conducted to derive an empirical significance of the magnitude of change in R2 between polygenic risk scores derived from the discovery sample of Tourette’s syndrome/chronic tics without OCD compared with those derived from the “all OCD” sample (OCD with or without Tourette’s syndrome/chronic tics). Second, risk alleles from each discovery sample were used to calculate the difference in polygenic risk scores between the transmitted (case) alleles and the untransmitted (pseudo-control) alleles in the OCD trio target sample. The degree of risk score elevation (risk scoretransmitted − risk scoreuntransmitted) was then standardized ([risk scoretransmitted − risk scoreuntransmitted]/risk scoreuntransmitted) and compared between different discovery samples using two-sided paired t tests. For further details of both approaches, see Supplementary Methods in the online data supplement.

Results

Combined Tourette’s Syndrome-OCD GWAS

The final combined Tourette’s syndrome-OCD data set consisted of 2,723 cases (1,310 with OCD, 834 with Tourette’s syndrome, 579 with OCD and Tourette’s syndrome/chronic tics), 5,667 controls, and 290 OCD trios. A total of 7,659,573 SNPs (439,840 genotyped and 7,219,733 imputed) were included in the meta-analysis. The genomic control λ showed no evidence of residual population stratification or systematic technical artifacts (λGC=1.030; see Figure S3 in the online data supplement).

Sixty-eight SNPs with p<1×10−5, representing 16 independent genomic regions, were identified, although none reached the genome-wide significance threshold of p<5×10−8 (Table 1, Figure 1; see also Table S1 in the online data supplement). The most significant association was found in rs4988462 on 3p11 (p=3.72×10−7, odds ratio=1.18). This SNP lies within an intron of POU1F1, although the entire 279-kb region of association in LD with rs4988462 contains 16 additional SNPs with p<1×10−5 and includes CHMP2B and POU1F1 as well as the microRNA MIR4795. Regional association and forest plots from the top five independent GWAS signals are provided in Figures S4–S8 in the data supplement. Eleven of the 68 SNPs were also identified in the original OCD GWAS with p<1×10−5; none of these SNPs were identified in the Tourette’s syndrome GWAS at p<1×10−5 (15, 16) (see Table S1 in the data supplement).

TABLE 1. Genomic Regions With p<1×10–5 in the Combined Tourette’s Syndrome-Obsessive-Compulsive Disorder (OCD) Genome-Wide Association Study (GWAS)a

ChrSNPA1/A2A1 FRQOdds RatioCombined GWAS pPosition (hg19)Number of SNPs in LDGenesTourette’s Syndrome GWAS pOCD GWAS p
3rs4988462T/C0.421.183.7×10–787,127,019–87,406,369343MIR4795, CHMP2B, POU1F11.1×10–34.9×10–5
11rs4271390T/C0.251.21.1×10–6119,514,810–119,537,68318PVRL11.1×10–34.4×10–5
13rs11149058C/T0.220.821.4×10–677,515,486–77,992,185135IRG1, CLN5, Mir_633, FBXL3, MYCBP21.6×10–53.1×10–3
3rs149183310T/A0.0441.521.5×10–6115,864,394–116,185,43677LSAMP3.1×10–33.4×10–5
3rs73070160T/C0.141.243.3×10–634,819,681–35,152,858152FECHP1.3×10–33.8×10–4
18rs12959570G/A0.231.23.9×10–654,247,051–54,522,865174TXNL1, WDR73.9×10–28.7×10–7
9rs7848024A/G0.271.195.3×10–6105,520,114–105,753,694248CYLC21.2×10–31.2×10–4
13rs6563569C/T0.441.165.7×10–638,087,567–38,290,276238POSTN, TRPC43.0×10–43.3×10–3
6rs859980T/C0.470.876.5×10–6104,462,081–104,517,07393LOC1001296948.6×10–35.0×10–5
9rs10973956A/C0.161.237.2×10–638,643,129–38,677,13629FAM201A5.6×10–41.0×10–3
2rs35881094G/T0.431.167.4×10–658,847,436–59,058,234122FLJ308385.9×10–47.6×10–4
11rs11021169T/G0.080.777.8×10–695,194,927–95,253,183165S_rRNA1.7×10–44.5×10–3
20rs55797066C/T0.061.338.1×10–650,165,634–50,442,18725NFATC2, ATP9A, SALL47.2×10–45.4×10–5
1rs7524258T/C0.41.168.4×10–67,250,522–7,352,14387CAMTA11.4×10–22.4×10–5
4rs61792199G/A0.151.238.6×10–622,833,517–22,935,71253GBA35.4×10–41.1×10–3
14rs1040832A/G0.21.219.9×10–693,247,868–93,374,78433GOLGA5, CHGA5.1×10–32.6×10–4

aChr=chromosome; SNP=single-nucleotide polymorphism; A1=reference allele; A2=alternative allele; A1 FRQ=frequency of A1 allele in the European-ancestry control samples; number of SNPs in LD=number of additional SNPs in linkage disequilibrium with association p values <1×10–3 (LD defined as r2>0.5). Complete annotation of these SNPs as well as all SNPs with association p values <1×10–3 is provided in Tables S1 and S2 in the online data supplement.

TABLE 1. Genomic Regions With p<1×10–5 in the Combined Tourette’s Syndrome-Obsessive-Compulsive Disorder (OCD) Genome-Wide Association Study (GWAS)a

Enlarge table
FIGURE 1.

FIGURE 1. Manhattan Plot of All Genotyped and Imputed Single-Nucleotide Polymorphisms for 3,013 Tourette’s Syndrome-Obsessive-Compulsive Disorder European Ancestry Cases and 5,957 Controlsa

a Red and blue lines indicate significance thresholds of 5×10−8 and 1×10−5, respectively.

Enrichment Analyses

For Tourette’s syndrome, OCD, and the combined sample, we examined the subset of disease association p values for SNPs meeting stringent criteria for eQTLs (peQTL <10−6) derived from cerebellum, parietal cortex, and frontal cortex, as well as cerebellar mQTLs (pmQTL <10−6) (Figure 2). Using the field standard false-discovery-rate threshold of <0.25, we identified 38 cerebellar eQTLs from five LD-independent loci for Tourette’s syndrome, 161 cerebellar mQTLs (19 LD-independent loci) for OCD, and 53 parietal cortex eQTLs (four LD-independent loci) for the combined GWAS (Table 2).

FIGURE 2.

FIGURE 2. Q-Q Plot of Nominal Disease Association p Values Versus Expected p Values Among the Cis eQTLs and mQTLs in Different Brain Tissues in the Tourette’s Syndrome, Obsessive-Compulsive Disorder (OCD), and Combined Genome-Wide Association Study (GWAS)a

a eQTL=expression quantitative trait locus; mQTL=methylation quantitative trait locus. A horizontal shift to the left from the diagonal line (of complete concordance between the observed p values and expected p values under the null hypothesis of no enrichment) in the Q-Q plot indicates enrichment. Red dots represent cerebellum mQTLs, green dots represent cerebellum eQTLs, black dots represent frontal cortex eQTLs, and blue dots represent parietal cortex eQTLs.

TABLE 2. Number of Associated eQTLs/mQTLs With False Discovery Rate <0.25 in the Tourette’s Syndrome, Obsessive-Compulsive Disorder (OCD), and Combined Genome-Wide Association Study (GWAS)a

Tourette’s Syndrome GWASOCD GWASCombined GWAS
TissueFunctional SubsetQTLsLociQTLsLociQTLsLoci
Frontal cortexeQTLs000000
Parietal cortexeQTLs0000534
CerebellumeQTLs3850000
CerebellummQTLs001611800

aeQTL=expression quantitative trait locus; mQTL=methylation quantitative trait locus. Number of loci indicates the number of LD-independent loci among the identified eQTLs.

TABLE 2. Number of Associated eQTLs/mQTLs With False Discovery Rate <0.25 in the Tourette’s Syndrome, Obsessive-Compulsive Disorder (OCD), and Combined Genome-Wide Association Study (GWAS)a

Enlarge table

Polygenic Risk Score Analysis

Polygenic score analyses were conducted to test two related hypotheses: 1) that both Tourette’s syndrome and OCD individually harbor multiple, small-effect, common risk alleles across the genome; and 2) that Tourette’s syndrome and OCD may have shared common risk alleles (cross-disorder analyses). In the individual disorder analyses, risk scores derived from the OCD without known co-occurring Tourette's syndrome/chronic tics discovery sample strongly predicted case-control status in the OCD target sample (p=2.1×10−4), explaining 3.2% of the phenotypic variance (Figure 3; see also Table S3 in the online data supplement). In contrast, risk scores derived from the Tourette’s syndrome discovery sample demonstrated only weak prediction in the Tourette’s syndrome target sample (p=0.06; R2=0.6% of variance explained). Risk scores derived from the combined Tourette’s syndrome-OCD discovery sample also predicted case-control status in the OCD target sample (p=0.0075, R2=1.7% of variance explained), although less robustly than those derived from the OCD discovery sample alone (p=0.01; see Figure 3, inset). Risk scores derived from the Tourette’s syndrome-OCD combined sample could not discriminate between cases and controls in the Tourette’s syndrome target sample (p=0.4; see Figure 3; see also Table S3 in the data supplement).

FIGURE 3.

FIGURE 3. Individual Disorder and Cross-Disorder Polygenic Score Analysis in Tourette’s Syndrome and Obsessive-Compulsive Disorder (OCD)a

a The variance explained in two target samples (OCD European ancestry [EU] parent-child trios and Tourette’s French Canadian [FC] cases and matching controls) is based on risk scores derived from an aggregated sum of weighted single-nucleotide polymorphism risk allele effect sizes estimated from discovery samples at six significance thresholds. The y axis indicates Nagelkerke’s pseudo R2. The p value under each discovery sample indicates how well the risk scores derived from the discovery sample can predict the illness phenotype in the target sample. N is the number of cases in each discovery sample. Negative R2 values indicate a negative correlation between risk scores and illness status in the target sample. OCD EU without known Tourette’s/chronic tics=European-ancestry OCD genome-wide association study (GWAS) samples after removing samples with known co-occurring Tourette’s/chronic tics; all OCD EU=European-ancestry OCD GWAS samples plus additional EU GWAS samples with co-occurring OCD and Tourette’s/chronic tics; combined Tourette’s/OCD EU=all European-ancestry Tourette’s GWAS samples and OCD GWAS samples; downsized OCD EU=randomly selected subset of OCD EU samples to match the number of cases in the Tourette’s EU discovery sample; Tourette’s EU=European-ancestry Tourette’s GWAS samples; OCD EU trios=the OCD EU parent-child trio probands and matched pseudo-control data derived from nontransmitted alleles; Tourette’s FC=Tourette’s French Canadian cases and matching controls. A permutation test was carried out to determine the significance of the difference in R2 between risk scores derived from OCD EU without known Tourette’s/chronic tics and all OCD EU, resulting in a two-sided empirical p value of 0.01. The inset box at upper right demonstrates the risk score elevations (difference in risk scores of transmitted alleles and untransmitted alleles in the OCD EU trios, standardized by the risk score of the untransmitted alleles) derived from three discovery samples: OCD EU without known Tourette’s/chronic tics, all OCD EU, and combined Tourette’s/OCD EU. Two-sided paired t tests were conducted for the pairwise comparisons of risk score elevations derived from three discovery samples.

In cross-disorder analyses, risk scores derived from the Tourette’s syndrome discovery sample did not predict case-control status in the OCD target sample (p=0.66), nor did OCD-associated risk scores predict into the Tourette’s syndrome target sample (p=0.37) (see Figure 3 and Table S3).

To explore the influence of phenotype comorbidity on polygenic risk score prediction, an additional all-OCD discovery sample was created that included the primary OCD discovery sample plus 345 additional case subjects with OCD plus co-occurring Tourette’s syndrome/chronic tics. As expected, the polygenic score using risk alleles derived from this discovery sample predicted case-control status in the OCD target sample (p=2.3×10−3) (Figure 3). However, the proportion of variance explained by the all-OCD risk score was significantly attenuated compared with the risk score derived from the primary OCD without co-occurring Tourette's syndrome/chronic tics discovery sample, despite the 30% increase in sample size (OCD without co-occurring Tourette's syndrome/chronic tics, N=1,154, R2=3.2% of variance explained; all-OCD sample, N=1,499, R2=2.1% of variance explained; permutation p=0.01; see Figure 3; see also Figure S9 in the data supplement).

In addition, the magnitude of elevation in the polygenic risk scores (risk score elevation) between transmitted and untransmitted risk alleles in the OCD trios was calculated using risk alleles from the different OCD discovery samples and compared (see Figure 3, inset). The risk score elevation in the OCD trios was highest when the primary OCD without co-occurring Tourette's syndrome/chronic tics discovery sample was used to derive the risk score compared to either the all-OCD sample or the combined Tourette’s syndrome-OCD sample (paired t test, p=0.022 and p=0.010, respectively), consistent with a dilution of risk when either OCD cases with Tourette’s syndrome/chronic tics or Tourette’s syndrome cases without OCD were incorporated in the discovery sample.

Discussion

Our goal in this study was to leverage phenotypic and genotypic data of two phenotypically related and frequently co-occurring neurodevelopmental disorders, Tourette’s syndrome and OCD, to explore the hypothesis that these disorders share common genetic susceptibility variants. Our strategy was 1) to combine the samples in a joint GWAS, 2) to examine their patterns of eQTL/mQTL enrichment, and 3) to explore cross-disorder polygenic signals. Although limited by small sample sizes, the results of these diverse analytic approaches suggest a complex genetic relationship between Tourette’s syndrome and OCD.

While our previous work with this sample provides evidence of genetic sharing between Tourette’s syndrome and OCD, with a genetic correlation of 0.41 between the two disorders (10), we did not identify any genome-wide significant variants for the combined Tourette’s syndrome-OCD phenotype in this GWAS analysis, despite the increase in sample size. However, the combined GWAS signals were significantly enriched for functional alleles (parietal eQTLs), suggesting that these subthreshold variants contain some proportion of Tourette’s syndrome-OCD risk loci that are not simply due to stochastic variation. In the presence of genetic heterogeneity (see below), this sample is underpowered to determine whether these loci contribute to susceptibility to both Tourette’s syndrome and OCD, or to susceptibility to one or the other individually. As with any genetic association result, replication in an independent sample is required to know whether any of the individual eQTLs identified here are truly shared Tourette’s syndrome-OCD susceptibility variants (9, 26, 27).

However, the results of the polygenic analyses do provide strong evidence that OCD and Tourette’s syndrome have at least some distinct genetic risk factors. First, the individual disorder analyses confirm that OCD has a significant polygenic component. The proportion of OCD variance explained by directly interrogated SNPs (3.2%) is similar to the findings in schizophrenia (3%–6%) and bipolar disorder (2.8%) (25), indicating that OCD likely arises from the joint influence of a large number of susceptibility genes spread across the genome, either as common variants or as rare variants in tight linkage disequilibrium with GWAS SNPs. This result is consistent with a parallel heritability study of the same data sets using mixed linear modeling, which found that OCD heritability is concentrated in common variants with minor allele frequencies >30% (10).

In contrast, the proportion of Tourette’s syndrome variance explained was substantially lower (0.6%). Although some of the difference in polygenic risk prediction between OCD and Tourette’s syndrome may be due to the smaller discovery sample size for Tourette’s syndrome, a sensitivity analysis in which the OCD discovery sample size was reduced to match that of the Tourette’s syndrome sample still detected a larger, and statistically significant, OCD polygenic signal than the comparable Tourette’s syndrome signal (p=0.01) (see Figure 3 and Table S3). The Tourette’s syndrome discovery sample was also too small to examine polygenic signals in Tourette’s syndrome subgroups (Tourette’s syndrome plus OCD versus Tourette's syndrome without OCD); thus, it is possible that the Tourette’s syndrome polygenic signal could increase if Tourette’s-syndrome-only discovery and target samples were available. The Tourette’s syndrome polygenic signal may also have been attenuated by restricting polygenic risk score SNPs to those with minor allele frequencies >5% (done to reduce bias due to undercalling of rare variants; see Supplementary Methods in the data supplement), as this class of SNPs has been shown to account for ∼20% of the variance in liability to Tourette’s syndrome, with 80% attributable to common variants (10). Both the investigation of Tourette’s syndrome subgroups and the analysis of polygenic signal including SNPs with minor allele frequencies ≤5% may be possible in the future as the number of subjects with available GWAS data increases.

The cross-disorder polygenic analyses also provide evidence for genetic heterogeneity between OCD and Tourette’s syndrome. First, the polygenic risk scores generated from the individual OCD and Tourette’s syndrome discovery samples did not predict case-control status of the other disorder. Second, the combined Tourette’s syndrome-OCD sample was a worse predictor of OCD or Tourette’s syndrome status than either disorder alone, suggesting that the degree of genetic heterogeneity generated by combining the two phenotypes outweighs any improvement in statistical power due to increased sample size. As noted above, however, our data are likely underpowered to detect a modest shared signal, which we have previously identified in this sample using a mixed-model approach (10).

Although we were not able to examine Tourette’s syndrome subgroups, we were able to examine the polygenic composition within OCD subgroups (OCD with or without Tourette’s syndrome/chronic tics). These results clearly suggest that OCD with and without chronic tics have different genetic architectures. When OCD cases with co-occurring Tourette’s syndrome/chronic tics were added to the OCD discovery sample, the polygenic signal in the independent OCD target sample was attenuated by 35% (permutation p=0.01), despite the 30% increase in sample size. Similarly, the risk score elevation between transmitted and untransmitted alleles dropped substantially with the addition of these 345 OCD cases with co-occurring Tourette’s syndrome/chronic tics (p=0.022).

The hypothesis that OCD may be genetically heterogeneous, with some individuals and families segregating OCD without tics and others a subtype of OCD with tics that may share genetic risk with Tourette’s syndrome, was originally proposed by Pauls et al. in 1986 (27), and more recent epidemiologic studies have provided additional support for this concept (9, 26, 28). Although not yet studied, these genetic differences may also correlate with well-documented differences in treatment outcomes of patients who have OCD alone compared with those who have OCD with tics, in which the latter are more refractory to treatment and may require augmentation with antipsychotics (29–31).

Limitations

The primary limitation of this study is related to sample size. While our study represents the largest genetic sample of either disorder studied to date, the total sample of 3,013 case subjects and 5,957 control subjects has 67% power to detect an illness variant with an odds ratio of 1.25 (assuming the risk allele frequency is 20% in the general population), and only 25% power to detect a variant with an odds ratio of 1.20. Recent studies of other psychiatric disorders with evidence of genetic overlap have required substantially larger sample sizes in order to detect individual variants that contribute to both disorders (32, 33). Therefore, caution is necessary when drawing conclusions about the genetic architecture of Tourette’s syndrome and OCD based exclusively on the results of the combined GWAS. However, we have more confidence in our interpretation of the polygenic analyses, which demonstrated significant differences between the aggregate polygenic risk for the Tourette’s syndrome-OCD phenotypes despite comparatively small sample sizes. Of note, aggregate polygenic signals have been successfully detected with a comparable number of subjects in other cross-disorder studies as well (32, 33).

In addition, although we propose that the differences in polygenic risk prediction between Tourette’s syndrome and OCD and between OCD with and without tics are due to divergent genetic architectures, alternative explanations should be considered, such as diagnostic misclassification or differences in case ascertainment between study sites or over time. It is also important to note that we focused on common variation, and that rare inherited variation, unique mutations within individual families, de novo mutations, structural variation, and epigenetic and nongenetic factors are all likely contributors to the overall etiology of these related disorders. While our initial studies suggested that common variants account for most of the heritability of Tourette’s syndrome and OCD (10), it is still critically important to explore all of these potential contributors to disease in order to acquire a full understanding of their relative contributions to Tourette’s syndrome and OCD.

Finally, interpretation of the eQTL/mQTL analyses is limited by the fact that the tissues analyzed represent a convenience sample based on currently available data, and hence conclusions about tissue specificity should be reserved until larger eQTL data sets across the full range of brain regions and developmental time periods are available.

Overall, our results argue that, in addition to some shared genetic variants contributing to susceptibility to either Tourette’s syndrome or OCD, genetic variants likely exist that provide phenotypic specificity for each disorder. This observation contrasts with the hypothesis that genes contributing to neuropsychiatric disorders provide a “generalist” framework of neuronal connections from which nongenetic factors determine specific phenotypes, as has been proposed to explain the wide range of phenotypes observed in patients with similar large recurrent copy number variants across various regions of the genome (34, 35). Furthermore, the apparent difference between OCD with and without tics supports the importance of detailed phenotypic characterization to identify subtype-specific risk alleles in the future. Collection of additional samples through ongoing collaboration will be crucial to further elucidate the specific underlying susceptibility genes for Tourette’s syndrome and OCD, both shared and unique.

From the Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetics Research, Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston; the Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, Mass.; the Department of Psychiatry, University of California, San Francisco; the Department of Neurology, Massachusetts General Hospital, Boston; the Division of Cognitive and Behavioral Neurology, Brigham and Women’s Hospital, Boston; the Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston; Section of Genetic Medicine, Department of Medicine, University of Chicago, Chicago; the Department of Psychiatry, Academic Medical Center, University of Amsterdam, Amsterdam; the Department of Preventive Medicine, Division of Biostatistics, Keck School of Medicine, University of Southern California, Los Angeles; the Laboratory of Neurogenetics, National Institute on Aging, Bethesda, Md.; the Genomic and Bioinformatic Unit, Filarete Foundation, Milan, Italy; the Department of Health Sciences, Graduate School of Nephrology, University of Milan, Milan; the Toronto Western Research Institute, University Health Network, Toronto; Hospital for Sick Children, Toronto; Università Vita-Salute San Raffaele, Milan; the Herman Dana Division of Child and Adolescent Psychiatry, Hadassah-Hebrew University Medical Center, Jerusalem; Universidad de Antioquia, Universidad Pontificia Bolivariana, Medellín, Colombia; the Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore; the Department of Psychiatry, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City; the Child Study Center and the Department of Psychiatry, Yale University School of Medicine, New Haven, Conn.; the Department of Psychiatry, University of São Paulo Medical School, São Paulo, Brazil; North Shore-Long Island Jewish Medical Center and North Shore-Long Island Jewish Health System, Manhasset, N.Y.; New York University Medical Center, New York; Hofstra University School of Medicine, Hempstead, N.Y.; Instituto Nacional de Psiquiatría Ramon de la Fuente Muñiz, Mexico City; University College London, London; the Department of Psychiatry, University of Hong Kong, Hong Kong; Ospedale San Raffaele, Milan; the Department of Psychiatry, University of California San Diego, La Jolla; the Department of Psychology, University of California Los Angeles; Montreal Neurological Institute, McGill University, Montreal; the Institute for Juvenile Research, Department of Psychiatry, University of Illinois at Chicago; Human Genetics and Cognitive Functions, Institut Pasteur, Paris; Fondation FondaMental, French National Science Foundation, Créteil, France; AP-HP, Robert Debré Hospital, Department of Child and Adolescent Psychiatry, Paris; Netherlands Institute for Neuroscience, Royal Netherlands Academy of Arts and Sciences, Amsterdam; the Department of Psychiatry, University of Montreal, Montreal; Infant Child and Adolescent Psychiatry, University of New South Wales, Australia; Academic Unit of Child Psychiatry, South West Sydney Local Health District (AUCS), Australia; Department of Child and Adolescent Psychiatry and Psychotherapy, University of Tübingen, Germany; the Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University of Würzburg, Würzburg, Germany; the Department of Psychiatry and Psychotherapy, University of Munich, Munich; Hospital Nacional de Niños, San Jose, Costa Rica; Clinica Herrera Amighetti, Avenida Escazú, San Jose, Costa Rica; OCD Program, Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston; Cincinnati Children’s Hospital Medical Center and University of Cincinnati, Cincinnati; the Department of Psychiatry and Psychotherapy, Helios-Hospital Stralsund, University Medicine Greifswald, Greifswald, Germany; the Department of Psychiatry and Human Behavior, Brown Medical School, Butler Hospital, Providence, R.I.; Neuropediatric Unit, Shaare Zedek Medical Center, Jerusalem; the University Clinics of Child and Adolescent Psychiatry, University of Zurich, Zurich, Switzerland; the Department of Genetics, Human Genetics Institute of New Jersey, Rutgers University, Piscataway; the Department of Psychiatry, University of Stellenbosch, Stellenbosch, South Africa; the Department of Psychiatry, University Medical Center, University of Groningen, Groningen, the Netherlands; Parkinson's Disease Center and Movement Disorders Clinic, Department of Neurology, Baylor College of Medicine, Houston; the Neurogenetics Section, Centre for Addiction and Mental Health, Toronto; the Department of Psychiatry, University of Toronto, Toronto; Atlantic Neuroscience Institute, Overlook Hospital, Summit, N.J.; Carracci Medical Group, Mexico City; Institut Mondor de Recherche Biomédicale, Psychiatric Genetics, Créteil, France; the Department of Psychiatry and Psychotherapy, University of Bonn, Bonn; the Department of Psychiatry, Institute of Human Genetics, University of Illinois at Chicago; MRC Unit on Anxiety and Stress Disorders, Departments of Psychiatry, University of Stellenbosch and University of Cape Town, South Africa; the Department of Psychiatry and Human Behavior, School of Medicine, University of California Irvine; Università Vita Salute San Raffaele and IRCCS San Raffaele Scientific Institute, Milan; the Center of Transfusion Medicine and Immunohematology, Foundation IRCCS Ca'Granda Ospedale Maggiore Policlinico, Milan; the Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles; David Geffen School of Medicine, Los Angeles; Department of Biological Sciences, Columbia University, New York; University of Utah, Salt Lake City; Laboratory of Clinical Science, NIMH Intramural Research Program, Bethesda, Md.; the Department of Clinical Research, Medical City Dallas Hospital, Dallas; the Department of Psychiatry, Rudolf Magnus Institute of Neuroscience, University Medical Center, Utrecht, the Netherlands; the Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles; the Department of Genetics, Yale University School of Medicine, New Haven, Conn.; the Department of Psychiatry and Behavioral Sciences, Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles; Partners Psychiatry and McLean Hospital, Boston; the Frederick W. Thompson Anxiety Disorders Centre, Sunnybrook Health Sciences Centre, Toronto; St. George’s Hospital and Medical School, London; the Child and Adolescent Psychiatry Unit, Department of Psychiatry, Federal University of São Paulo, Brazil; the Department of Psychiatry and Behavioral Neurosciences, Wayne State University and the Detroit Medical Center, Detroit; the Department of Psychiatry and Psychotherapy, University of Cologne, Cologne, Germany; the Department of Health Research and Policy, Stanford University, Stanford; University Health Care Services-SMURB, Universidade Federal da Bahia, Salvador, Bahia, Brazil; the Department of Psychiatry, University of Toronto and University Health Network, Toronto Western Research Institute and Youthdale Treatment Centers, Toronto; Johns Hopkins University School of Medicine, Baltimore; the Department of Psychiatry, VU University Medical Center, Amsterdam; University of Cape Town, Cape Town, South Africa; the Department of Medical Genetics, University Medical Center Utrecht, Utrecht, the Netherlands; the Department of Health Technologies, University of Milan, Milan; the Departments of Psychiatry, Pediatrics, and Pharmacology, Kennedy Center for Research on Human Development, and Brain Institute, Vanderbilt University, Nashville, Tenn.; the Department of Child and Adolescent Psychiatry, University of Würzburg, Würzburg, Germany; the Division of Child and Adolescent Psychiatry, Department of Psychiatry, Weill Cornell Medical Center, New York; the Department of Medical and Molecular Genetics, King’s College London, London; the Department of Psychiatry, Academic Medical Center and Netherlands Institute for Neuroscience, Royal Netherlands Academy of Arts and Sciences, Amsterdam; Unit on Statistical Genomics, NIMH Intramural Research Program, Bethesda, Md.; National Institute of Genomic Medicine-SAP, Carracci Medical Group, Mexico City; the Department of Clinical and Health Psychology, Utrecht University, Utrecht, the Netherlands; the Department of Psychiatry, University of Utah, Salt Lake City; Section of Medical Genomics, Department of Clinical Genetics, VU University Medical Center, Amsterdam; the Department of Functional Genomics, Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, VU University Amsterdam, Amsterdam; the Department of Child and Adolescent Psychiatry and the Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, the Netherlands; Mt. Sinai Medical Center, New York; the German Center for Neurodegenerative Diseases, Tübingen; the Department of Psychiatry, University of Michigan, Ann Arbor; Program in Genetics and Genome Biology, Hospital for Sick Children, Toronto; British Columbia Mental Health and Addictions Research Institute, University of British Columbia, Vancouver.
Address correspondence to Ms. Yu () and Dr. Pauls ().

The first three authors and the last four authors contributed equally to this work.

Dr. Westenberg is deceased.

Supported by a grant from the David Judah Fund; NIH grant NS40024 to Drs. Pauls and Scharf; the Tourette Syndrome Association International Consortium for Genetics; NIH grants NS16648, MH079489, and MH073250 to Dr. Pauls; NIH grant NS037484 to Dr. Freimer; a grant from the Tourette Syndrome Association and NIH grant MH085057 to Dr. Scharf, grant MH079494 to Dr. Knowles, MH71507 to Dr. McCracken; the OCD Collaborative Genetics Association Study, which supported the imputation; an American Academy of Child and Adolescent Psychiatry Early Investigator Research Grant, an Anxiety Disorders Association of America Junior Investigator Research Grant, the University of British Columbia, and a Michael Smith Foundation Clinical Research Scholar Award to Dr. Stewart; American Recovery and Reinvestment Act awards NS40024-07S1 to Drs. Pauls and Scharf and NS16648-29S1 to Dr. Pauls. Additional support for analysis was provided by grants R01 MH090937 and P50MH094267 to Dr. Cox and by grant P30NS062691 from the UCLA Informatics Center for Neurogenetics and Neurogenomics to Dr. Freimer. Dr. Heiman and Dr. Tischfield received support from the New Jersey Center for Tourette Syndrome and Associated Disorders and NIMH grant R01MH092293. Dr. Stein and Dr. Lochner are supported by the Medical Research Council of South Africa. Funding support for the Study of Addiction: Genetics and Environment (SAGE) was provided through the NIH Genes, Environment, and Health Initiative [GEI] (grant U01 HG004422). SAGE is one of the genome-wide association studies funded as part of the Gene Environment Association Studies (GENEVA) under GEI. Assistance with phenotype harmonization and genotype cleaning, as well as with general study coordination, was provided by the GENEVA Coordinating Center (grant U01 HG004446). Assistance with data cleaning was provided by the National Center for Biotechnology Information. Support for collection of data sets and samples was provided by the Collaborative Study on the Genetics of Alcoholism (grant U10 AA008401), the Collaborative Genetic Study of Nicotine Dependence (grant P01 CA089392), and the Family Study of Cocaine Dependence (grant R01 DA013423). Funding support for genotyping, which was performed at the Johns Hopkins University Center for Inherited Disease Research, was provided by the NIH GEI (grant U01HG004438), the National Institute on Alcohol Abuse and Alcoholism, the National Institute on Drug Abuse, and the NIH contract “High Throughput Genotyping for Studying the Genetic Contributions to Human Disease” (grant HHSN268200782096C). The data sets used for the analyses in this study were obtained from dbGaP at http://www.ncbi.nlm.nih.gov/projects/gap/cgibin/study.cgi?study_id=phs000092.v1.p1 through dbGaP accession number phs000092.v1.p. The European Union (grant FP7-HEALTH-2007-A-201550), HYPERGENES, and InterOmics (PB05 MIUR-CNR Italian Flagship Project) provided financial support for the genotyping of Italian controls.

Dr. Scharf has received research support and travel support from the Tourette Syndrome Association (TSA); he also serves on the TSA Scientific Advisory Board. Dr. Black receives research support from AstraZeneca and royalties from American Psychiatric Publishing, Oxford University Press, and UpToDate. Dr. Budman has received research grant support from Psyadon, AstraZeneca, and Otsuka, and has served as a speaker for the National Tourette Syndrome Association-CDC Partnership. Dr. Cook served as a consultant and was a site principal investigator for a Seaside Therapeutics clinical trial in autism spectrum disorder. Dr. Coric is an employee of Bristol-Myers Squibb and owns stock in the company; his regarding this study stems from his work at Yale University, and no financial or other support for this study was obtained from Bristol-Myers Squibb. Dr. Denys received a grant from the U.S. national Tourette Syndrome Association; he is a member of the advisory board of Lundbeck and he receives consultant fees from Medtronic for educational purposes. Dr. Fernandez has received research funding from NIMH, the Simons Foundation, the Allison Foundation, and Shire. Dr. Gilbert has served as a site investigator for clinical trials in Tourette’s syndrome for Otsuka, Psyadon, and AstraZeneca. Dr. Grabe has received research support from the German Research Foundation, the Federal Ministry of Education, and Research Germany and has received speaking honoraria from Servier and Eli Lilly. Dr. Hardy has served as a consultant for Eisai and has been on speakers bureaus for Takeda, Eli Lilly, and Roche. Dr. Kennedy has received honoraria from Roche, Novartis, and Eli Lilly; he serves as an non-paid member of AssureRx Health Scientific Advisory Board. Dr. Leckman has received research support from NIH, the Tourette Syndrome Association, Grifols, and Klingenstein Third Generation Foundation, and royalties from John Wiley & Sons, McGraw-Hill, Oxford University Press. Dr. Piacentini has received research support from Pfizer Pharmaceuticals via the Duke University Clinical Research Institute and from the Tourette Syndrome Association; speaking/travel support from the Tourette Syndrome Association and the International OCD Foundation; financial support from the Pettit Family Foundation; and royalties from Oxford University Press and Guilford Press. Dr. Pittenger has served as a consultant for Roche. Dr. Rauch has participated in research funded by Medtronic and Cyberonics. Dr. Richter has received speaking honoraria from Lundbeck. Dr. Robertson has received support from the U.K. Tourette Syndrome Association, the U.S. Tourette Syndrome Association, and COST/ESSTS (the European Society for the Study of Tourette Syndrome); speaking honoraria from Janssen-Cilag and Flynn Pharma; and royalties from Wiley-Blackwell, Oxford University Press, David Fulton/Granada/Taylor Francis, and Jessica Kingsley Publishers. Dr. Rosário has served on speakers bureaus for Novartis and Shire. Dr. Rosenberg has served as a consultant for Shire. Dr. Ruhrmann has received speaking honoraria from Roche, Otsuka, Lundbeck, and Johnson & Johnson and travel funds from Roche and Servier. Dr. Sandor has received research support from Otsuka and speaking honoraria from Purdue Pharma. Dr. Stein has received research grants from and/or served as a consultant to AMBRF, Biocodex, Cipla, Lundbeck, National Responsible Gambling Foundation, Novartis, Servier, and Sun. Dr. Veenstra-VanderWeele has served as a consultant for Novartis, Roche, and SynapDx and received research funding from Novartis, Roche, SynapDx, Seaside Therapeutics, Forest, and Sunovion. Dr. Walitza has received speaking honoraria from Janssen Cilag, AstraZeneca, and Eli Lilly. Dr. Wendland is a former employee of Hoffmann-La Roche (2010–2012) and is now an employee of Pfizer (2012–present). Dr. Nicolini has received research funds from Pherin Pharmaceuticals, Transcept Pharmaceuticals, and EnVivo and speaking honoraria from MSD and Landsteiner Mexico. Dr. Arnold has received an unrestricted research grant from DNA Genotek. Dr. Knowles received a speaking honorarium from Illumina, Inc. Dr. McCracken has received research support from and/or served as a consultant to Roche, Seaside Therapeutics, and BioMarin. The other authors report no financial relationships with commercial interests.

The authors thank the families, patients, and control volunteers who participated in this research.

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