Obsessive-compulsive Disorder Probands Research Articles

Clinical characteristics of probands with obsessive-compulsive disorder from simplex and multiplex families

Genetic and non-genetic factors contribute to obsessive-compulsive disorder (OCD), with strong evidence of familial clustering. Genomic studies in psychiatry have used the concepts of families that are "simplex" (one affected) versus "multiplex" (multiple affected). Our study compares demographic and clinical data from OCD probands in simplex and multiplex families to uncover potential differences. We analyzed 994 OCD probands (501 multiplex, 493 simplex) from the Brazilian Research Consortium on Obsessive-Compulsive Spectrum Disorders (C-TOC). Clinicians administered the Structured Clinical Interview for DSM-IV (SCID-IV) to diagnose, Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) to assess severity, and Dimensional Yale–Brown Obsessive-Compulsive Scale (DY-BOCS) to assess symptom dimensionality. Demographics, clinical history, and family data were collected. Compared to simplex probands, multiplex probands had earlier onset, higher sexual/religious and hoarding dimensions severity, increased comorbidity with other obsessive-compulsive-related disorders (OCRD), and higher family history of psychiatric disorders. These comparisons provide the first insights into demographic and clinical differences between Latin American simplex and multiplex families with OCD. Distinct clinical patterns may suggest diverse genetic and environmental influences. Further research is needed to clarify these differences, which have implications for symptom monitoring and management.

The genomics of visuospatial neurocognition in obsessive-compulsive disorder: A preliminary GWAS

BackgroundThe study of Obsessive-Compulsive Disorder (OCD) genomics has primarily been tackled by Genome-wide association studies (GWAS), which have encountered troubles in identifying replicable single nucleotide polymorphisms (SNPs). Endophenotypes have emerged as a promising avenue of study in trying to elucidate the genomic bases of complex traits such as OCD. MethodsWe analyzed the association of SNPs across the whole genome with the construction of visuospatial information and executive performance through four neurocognitive variables assessed by the Rey-Osterrieth Complex Figure Test (ROCFT) in a sample of 133 OCD probands. Analyses were performed at SNP- and gene-level. ResultsNo SNP reached genome-wide significance, although there was one SNP almost reaching significant association with copy organization (rs60360940; P = 9.98E-08). Suggestive signals were found for the four variables at both SNP- (P < 1E-05) and gene-levels (P < 1E-04). Most of the suggestive signals pointed to genes and genomic regions previously associated with neurological function and neuropsychological traits. LimitationsOur main limitations were the sample size, which was limited to identify associated signals at a genome-wide level, and the composition of the sample, more representative of rather severe OCD cases than a population-based OCD sample with a broad severity spectrum. ConclusionsOur results suggest that studying neurocognitive variables in GWAS would be more informative on the genetic basis of OCD than the classical case/control GWAS, facilitating the genetic characterization of OCD and its different clinical profiles, the development of individualized treatment approaches, and the improvement of prognosis and treatment response.

Phenotypic Impact of Rare Potentially Damaging Copy Number Variation in Obsessive-Compulsive Disorder and Chronic Tic Disorders.

Background: Recent studies report an important—and previously underestimated—role of rare variation in risk of obsessive-compulsive disorder (OCD) and chronic tic disorders (CTD). Using data from a large epidemiological study, we evaluate the distribution of potentially damaging copy number variation (pdCNV) in OCD and CTD, examining associations between pdCNV and the phenotypes of probands, including a consideration of early- vs. late-diagnoses. Method: The Obsessive-Compulsive Inventory-Revised (OCI-R) questionnaire was used to ascertain psychometric profiles of OCD probands. CNV were identified genome-wide using chromosomal microarray data. Results: For 993 OCD cases, 86 (9%) were identified as pdCNV carriers. The most frequent pdCNV found was at the 16p13.11 region. There was no significant association between pdCNV and the OCI-R total score. However, pdCNV was associated with Obsessing and Checking subscores. There was no significant difference in pdCNV frequency between early- vs. late-diagnosed OCD probands. Of the 217 CTD cases, 18 (8%) were identified as pdCNV carriers. CTD probands with pdCNV were significantly more likely to have co-occurring autism spectrum disorder (ASD). Conclusions: pdCNV represents part of the risk architecture for OCD and CTD. If replicated, our findings suggest pdCNV impact some OCD symptoms. Genes within the 16p13.11 region are potential OCD risk genes.

Neurocognitive endophenotypes in pediatric OCD probands, their unaffected parents and siblings

BackgroundLimited extant research on neurocognitive endophenotypes in obsessive-compulsive disorder (OCD) show inconsistent results. Limitations of this body of literature include small sample sizes, strict exclusion criteria, lack of objective standard normalized test scores, and significant lack of studies utilizing pediatric probands. This study aimed to address these limitations. MethodsA large carefully screened cohort of pediatric OCD (n = 102), their unaffected siblings (n = 78), and parents (n = 164), completed a neuropsychological battery. To compare participants at different ages and developmental stages, standard scores were computed using test norms. Cluster-robust regression with sample size-adjusted sandwich estimates of variance, and interclass correlations were computed. False Discovery Rate procedures were employed to correct for multiplicity. ResultsProbands, siblings and parents demonstrated deficient task performance (Z < −0.5) on the ‘number of trials to complete first category’ on the Wisconsin Card Sorting Test, and on the Stroop color naming trials. Compared to test norms, the three groups exhibited medium to large effect sizes on these outcome measures. No other meaningful familial trends were found. ConclusionsOCD probands, their unaffected siblings and parents exhibited deficiencies in specific subdomains of cognitive flexibility and inhibitory control, namely, initial concept formation and proactive control, which may be valid candidate neurocognitive endophenotypes of OCD. No other meaningful familial effect has been found on other functions, including other executive function indices such as perseverations and interference control. These results highlight the need to carefully examine individual outcomes from executive function tests instead of the tendency to focus largely on major outcome measures.

Familial coaggregation of major psychiatric disorders among first-degree relatives of patients with obsessive-compulsive disorder: a nationwide study.

Whether the first-degree relatives (FDRs) of patients with obsessive-compulsive disorder (OCD) have an increased risk of the major psychiatric disorders, namely schizophrenia, bipolar disorder, OCD, major depressive disorder (MDD), autism spectrum disorder (ASD), and attention deficit hyperactivity disorder (ADHD), remains unclear. Using the Taiwan National Health Insurance Research Database with the whole population sample size (n = 23 258 175), 89 500 FDRs, including parents, offspring, siblings, and twins, of patients with OCD were identified in our study. The relative risks (RRs) of major psychiatric disorders were assessed among FDRs of patients with OCD. FDRs of patients with OCD had higher RRs of major psychiatric disorders, namely OCD (RR 8.11, 95% confidence interval (CI) 7.68-8.57), bipolar disorder (RR 2.85, 95% CI 2.68-3.04), MDD (RR 2.67, 95% CI 2.58-2.76), ASD (RR 2.38, 95% CI 2.10-2.71), ADHD (RR 2.19, 95% CI 2.07-2.32), and schizophrenia (RR 1.97, 95% CI 1.86-2.09), compared with the total population. Different familial kinships of FDRs, such as parents, offspring, siblings, and twins consistently had increased risks for these disorders. In addition, a dose-dependent relationship was found between the numbers of OCD probands and the risk of each major psychiatric disorder. The FDRs, including parents, offspring, siblings, and twins, of patients with OCD have a higher risk of OCD, schizophrenia, bipolar disorder, MDD, ADHD, and ASD. The familial co-aggregation of OCD with OCD and other major psychiatric disorders was existent in a dose-dependent manner. Given the increased risks of psychiatric disorders, medical practitioners should closely monitor the mental health of the FDRs of patients with OCD.

Genetic Associations of Serotoninergic and GABAergic Genes in an Extended Collection of Early-Onset Obsessive-Compulsive Disorder Trios.

Obsessive-compulsive disorder (OCD) is a debilitating neuropsychiatric disorder whose etiology includes important genetic contributions. In a previous transmission disequilibrium study in which 75 complete trios were included, single-nucleotide polymorphisms (SNPs) in serotoninergic and GABAergic genes were associated with early-onset OCD. Our aim was to assess those findings in an extended collection of early-onset OCD trios. A transmission disequilibrium test for SNPs in HTR1B (rs2000292), SLC18A1 (rs6586896), GAD1 (rs3791860), and GAD2 (rs8190748) was performed in a total of 101 early-onset OCD trios, from which 26 trios were newly recruited for the purpose of the present analysis. All the SNPs were overtransmitted from parents to OCD probands (p < 0.012, significant after Bonferroni correction). These results are consistent with the previous findings and constitute more evidence of the role of genetic factors related to serotoninergic and GABAergic pathways in the pathophysiology of early-onset OCD.

Prevalence of Obsessive-Compulsive Spectrum Disorders in Obsessive-Compulsive Disorder.

Introduction:There is growing awareness of the heterogeneity of obsessive-compulsive disorder (OCD) and of the multiple systems involved in its pathogenesis. Identification of obsessive-compulsive spectrum disorders (OCSDs) may have important implications in the management and prognosis of OCD, but there is a paucity of research in the domain of identification of OCSD in probands with OCD. There are few studies that have examined OCSD in the first-degree relatives (FDR) of OCD patients, some of these were not controlled, and these studies have no final agreements over outcomes, and therefore, this area needs to be further explored.Objectives:The objective of this study was to assess the prevalence of OCSDs in OCD probands; and its relationship to sociodemographic and clinical variables, comparing each aspect by a control group of schizophrenia probands.Materials and Methods:Sixty patients each of OCD and schizophrenia, diagnosed by the Diagnostic and Statistical Manual of Mental Disorders IV Text Revision,[1] above 18 years of age and giving informed consent, were interviewed using the Structured Clinical Interview for OCSD, Yale–Brown Obsessive-Compulsive Rating Scale, Hamilton Rating Scale for Depression, and Hamilton Rating Scale for Anxiety.Results:In OCD group, 22 OCSDs were found in 11 subjects whereas in schizophrenia group, 2 OCSDs (self-injury) were found in two probands. When the two groups were compared in terms of individual OCSDs, there was no significant difference between them. However, when the comparison was made taking into account all OCSDs taken together, it was significantly higher (P = 0.016) in the OCD group compared to the schizophrenia group.Conclusion:OCSDs were significantly more in OCD probands as compared to schizophrenia probands. This suggests a familial aggregation of these disorders.

A total-population multigenerational family clustering study of autoimmune diseases in obsessive-compulsive disorder and Tourette's/chronic tic disorders.

The association between obsessive-compulsive disorder (OCD) and Tourette's/chronic tic disorders (TD/CTD) with autoimmune diseases (ADs) is uncertain. In this nationwide study, we sought to clarify the patterns of comorbidity and familial clustering of a broad range of ADs in individuals with OCD, individuals with TD/CTD and their biological relatives. From a birth cohort of 7 465 455 individuals born in Sweden between 1940 and 2007, we identified 30 082 OCD and 7279 TD/CTD cases in the National Patient Register and followed them up to 31 December 2013. The risk of 40 ADs was evaluated in individuals with OCD, individuals with TD/CTD and their first- (siblings, mothers, fathers), second- (half siblings) and third-degree (cousins) relatives, compared with population controls. Individuals with OCD and TD/CTD had increased comorbidity with any AD (43% and 36%, respectively) and many individual ADs. The risk of any AD and several individual ADs was consistently higher among first-degree relatives than among second- and third-degree relatives of OCD and TD/CTD probands. The risk of ADs was very similar in mothers, fathers and siblings of OCD probands, whereas it tended to be higher in mothers and fathers of TD/CTD probands (compared with siblings). The results suggest a familial link between ADs in general (that is, not limited to Streptococcus-related conditions) and both OCD and TD/CTD. Additional mother-specific factors, such as the placental transmission of antibodies, cannot be fully ruled out, particularly in TD/CTD.

Executive function predicts cognitive-behavioral therapy response in childhood obsessive-compulsive disorder

Cognitive-behavioral therapy (CBT) is considered first-line treatment for childhood obsessive-compulsive disorder (OCD). Despite CBT's efficacy, too many children and adolescents do not fully respond to treatment, making the identification of predictors of treatment response highly relevant. Executive functions (EF) have been suggested to constitute such predictors, but studies with pediatric samples are scarce. In the present study, we investigated latent level EF test performance and ratings of daily life EF behavior as predictors of CBT response in pediatric OCD. We further examined the stability of EF from pre-to post-treatment and the association of EF changes with OCD severity change. EF test performance significantly predicted exposure-based CBT outcome. Patients with better EF test performance had significantly elevated risk of non-response relative to patients with poorer performance. Daily life EF behavior in OCD probands improved after treatment relative to controls. The findings suggest that EF performance impacts CBT outcome, and that exposure-based CBT is well-suited for children and adolescents with OCD and poorer EF test performance. This study supports the relevance of EF in CBT for childhood OCD and denotes a possible need for development of enhanced treatments for children and adolescents with OCD and superior EF performance.

Whole-exome sequencing in obsessive-compulsive disorder identifies rare mutations in immunological and neurodevelopmental pathways.

Studies of rare genetic variation have identified molecular pathways conferring risk for developmental neuropsychiatric disorders. To date, no published whole-exome sequencing studies have been reported in obsessive-compulsive disorder (OCD). We sequenced all the genome coding regions in 20 sporadic OCD cases and their unaffected parents to identify rare de novo (DN) single-nucleotide variants (SNVs). The primary aim of this pilot study was to determine whether DN variation contributes to OCD risk. To this aim, we evaluated whether there is an elevated rate of DN mutations in OCD, which would justify this approach toward gene discovery in larger studies of the disorder. Furthermore, to explore functional molecular correlations among genes with nonsynonymous DN SNVs in OCD probands, a protein–protein interaction (PPI) network was generated based on databases of direct molecular interactions. We applied Degree-Aware Disease Gene Prioritization (DADA) to rank the PPI network genes based on their relatedness to a set of OCD candidate genes from two OCD genome-wide association studies (Stewart et al., 2013; Mattheisen et al., 2014). In addition, we performed a pathway analysis with genes from the PPI network. The rate of DN SNVs in OCD was 2.51 × 10−8 per base per generation, significantly higher than a previous estimated rate in unaffected subjects using the same sequencing platform and analytic pipeline. Several genes harboring DN SNVs in OCD were highly interconnected in the PPI network and ranked high in the DADA analysis. Nearly all the DN SNVs in this study are in genes expressed in the human brain, and a pathway analysis revealed enrichment in immunological and central nervous system functioning and development. The results of this pilot study indicate that further investigation of DN variation in larger OCD cohorts is warranted to identify specific risk genes and to confirm our preliminary finding with regard to PPI network enrichment for particular biological pathways and functions.

Role of GAD2 and HTR1B genes in early‐onset obsessive‐compulsive disorder: results from transmission disequilibrium study

One of the leading biological models of obsessive-compulsive disorder (OCD) is the frontal-striatal-thalamic model. This study undertakes an extensive exploration of the variability in genes related to the regulation of the frontal-striatal-thalamic system in a sample of early-onset OCD trios. To this end, we genotyped 266 single nucleotide polymorphisms (SNPs) in 35 genes in 84 OCD probands and their parents. Finally, 75 complete trios were included in the analysis. Twenty SNPs were overtransmitted from parents to early-onset OCD probands and presented nominal pointwise P < 0.05 values. Three of these polymorphisms achieved P < 2 × 10(-4), the significant P-value after Bonferroni corrections: rs8190748 and rs992990 localized in GAD2 and rs2000292 in HTR1B. When we stratified our sample according to gender, different trends were observed between males and females. In males, SNP rs2000292 (HTR1B) showed the lowest P-value (P = 0.0006), whereas the SNPs in GAD2 were only marginally significant (P = 0.01). In contrast, in females HTR1B polymorphisms were not significant, whereas rs8190748 (GAD2) showed the lowest P-value (P = 0.0006). These results are in agreement with several lines of evidence that indicate a role for the serotonin and γ-Aminobutyric acid (GABA) pathways in the risk of early-onset OCD and with the gender differences in OCD pathophysiology reported elsewhere. However, our results need to be replicated in studies with larger cohorts in order to confirm these associations.

Population-Based, Multigenerational Family Clustering Study of Obsessive-compulsive Disorder

Controlled family studies have consistently found that obsessive-compulsive disorder (OCD) aggregates in families but have typically relied on samples recruited from specialist clinics. Furthermore, previous studies could not disentangle genetic from environmental factors contributing to the observed familiality. To provide unbiased estimates of familial risk for and heritability of OCD at the population level. Population-based, multigenerational, case-control family and twin studies using the Swedish National Patient Register, Multi-Generation Register, and Twin Register. All individuals diagnosed as having OCD between January 1, 1969, and December 31, 2009 (n = 24 768) and all their available first-, second-, and third-degree relatives, as well as nonbiological relatives and matched general population control subjects. Twins (n = 16 383) were included from the population-based Twin Register. The risk for OCD among relatives of OCD probands. The risk for OCD among relatives of OCD probands increased proportionally to the degree of genetic relatedness. The risk for first-degree relatives was significantly higher than that for second- and third-degree and nonbiological relatives. Second-degree relatives had higher risk for OCD than third-degree relatives. Relatives at similar genetic distances had similar risks for OCD, despite different degrees of shared environment. Separate twin modeling analyses confirmed that familial risk for OCD was largely attributable to additive genetic factors (47%; 95% CI, 42%-52%), with no significant effect of shared environment. Nonbiological relatives (spouses or partners who have at least 1 child together) also had an elevated risk for OCD (odds ratio, 2.61; 95% CI, 1.99-3.42). Early-onset probands (3907 individuals; mean age, 13.7 years) had slightly (nonsignificantly) higher familial risk than the total sample, although this was substantially lower than previously reported. There were no significant sex differences in the familial pattern or heritability estimates. Obsessive-compulsive disorder clusters in families primarily due to genetic factors. Nonshared environmental factors are at least as important. The quest for candidate genes, nonshared environmental risk factors, and their possible correlation or interaction should continue. The finding of possible assortative mating in OCD is intriguing and should be investigated further.

A blind re-analysis of the Iowa family study of obsessive-compulsive disorder

We present results from a re-analysis of the Iowa family study of obsessive-compulsive disorder (OCD) that previously concluded the disorder was not familial. These conclusions were based on Diagnostic Interview Schedule results of first-degree relatives (FDRs) and not a best estimate diagnosis (BED). For the re-analysis we reviewed raw data on OCD and control probands and their FDRs. Relatives had been assessed through structured interviews, validated questionnaires, family history, and medical records in some cases. BEDs were assigned through a blind consensus procedure employing DSM-IV criteria. The data were analyzed using logistic regression with generalized estimating equations to account for within family correlations. BEDs were assigned to 32 OCD probands, 31 control probands, and 352 FDRs, including 249 FDRs who were interviewed directly and 103 FDRs who were unavailable or deceased. Lifetime prevalence of definite/probable OCD was significantly higher in the FDRs of OCD probands than controls (10.7% vs. 3.8%, OR=3.04, p=0.026). FDRs of OCD probands had significantly higher rates of depressive illness than relatives of controls. Depression of any type in relatives was predicted by the proband's depression history. We conclude that OCD is familial. The re-analysis highlights the importance of the BED procedure in family studies.

Rare missense neuronal cadherin gene (CDH2) variants in specific obsessive-compulsive disorder and Tourette disorder phenotypes

The recent finding that the neuronal cadherin gene CDH2 confers a highly significant risk for canine compulsive disorder led us to investigate whether missense variants within the human ortholog CDH2 are associated with altered susceptibility to obsessive-compulsive disorder (OCD), Tourette disorder (TD) and related disorders. Exon resequencing of CDH2 in 320 individuals identified four non-synonymous single-nucleotide variants, which were subsequently genotyped in OCD probands, Tourette disorder probands and relatives, and healthy controls (total N=1161). None of the four variants was significantly associated with either OCD or TD. One variant, N706S, was found only in the OCD/TD groups, but not in controls. By examining clinical data, we found there were significant TD-related phenotype differences between those OCD probands with and without the N845S variant with regard to the co-occurrence of TD (Fisher's exact test P=0.014, OR=6.03). Both N706S and N845S variants conferred reduced CDH2 protein expression in transfected cells. Although our data provide no overall support for association of CDH2 rare variants in these disorders considered as single entities, the clinical features and severity of probands carrying the uncommon non-synonymous variants suggest that CDH2, along with other cadherin and cell adhesion genes, is an interesting gene to pursue as a plausible contributor to OCD, TD and related disorders with repetitive behaviors, including autism spectrum disorders.

P02-374 - Lack of mental flexibility as endophenotype in autism spectrum disorder and obsessive comulsive disorder families

IntroductionResults from clinical and molecular genetic studies suggest that autism spectrum disorder (ASD) and obsessive compulsive disorder (OCD) could have a shared pattern of heritability. Among a large number of clinical variables evaluated, obsessive compulsive/repetitive behaviors have been found to be highly correlated among autism probands and their relatives. Empirical evidence from neuropsychological studies suggest that an appropriate model for repetitive behaviours is a deficit of executive functions specifically flexibility. Given the lack of flexibility observed in ASD and OCD probands, we hypothesised that it could represent a shared endophenotype in both families.MethodsSeven cognitive tests belonging to executive functions, central coherence and theory of mind were proposed to 58 unaffected first-degree relatives of probands with ASD and 61 unaffected first-degree relatives of OCD patients and compared with 34 healthy controls. A principal component analysis (PCA) was performed.ResultsASD relatives - specifically mothers - performed significantly worse on all the tests than OCD relatives and controls. Moreover, inside the OCD group, female individuals performed significantly worse than males. Finally, the PCA indicate that the cognitive profiles of the ASD relatives and the OCD relatives were similar but distinct from controls.ConclusionLack of cognitive flexibility is observed in ASD and OCD families and might constitute a shared intermediate cognitive phenotype. Our study constitutes an effort to clarify the relationship between ASD and OCD having implications for our nosological understanding of both disorders.

Executive Dysfunctions in Obsessive-Compulsive Patients and Unaffected Relatives: Searching for a New Intermediate Phenotype

Evidence in literature suggests that neurocognitive deficits may represent suitable intermediate-phenotype candidates for the dissection of obsessive-compulsive disorder (OCD) genetic heterogeneity. The aim of this study was to search for possible OCD neurocognitive endophenotypes by assessing decision-making, planning, and mental flexibility profiles in OCD probands, healthy control subjects (HC), and their respective relatives. The sample consisted of 35 pairs of OCD probands without other Axis I comorbidities and unaffected first-degree relatives and 31 pairs of HC subjects without a known family history of OCD and their relatives. Neuropsychological assessment was performed using the Iowa Gambling Task (IGT), the Tower of Hanoi (ToH), and the Wisconsin Card Sorting Test (WCST). Obsessive-compulsive disorder patients showed impairments in decision making, planning, and mental flexibility, given that OCD probands performed significantly poorer than HC probands at the IGT, the ToH, and the WCST. Obsessive-compulsive disorder relatives performed poorer at these tests than HC probands and relatives. Symptom severity was found to have no influence on neurocognitive performance. Analysis of proband/relative concordance in task performance was performed for each task. A significant overall difference was found when comparing the percentages of the different concordance profiles of our OCD and HC samples with regard to IGT and ToH performance. No significant difference was found in the WCST. Executive dysfunctions may qualify as a suitable endophenotype candidate for OCD. Concordance rates in neuropsychological task performance suggest that decision-making and planning deficits aggregate in these families and therefore might be a heritable component of OCD.

Reduced 3‐O‐methyl‐dopa levels in OCD patients and their unaffected parents is associated with the low activity M158 COMT allele

The catechol-O-methyltransferase (COMT) gene is considered as a candidate gene in obsessive-compulsive disorder (OCD). Specifically, the COMT low-activity M158 allele has been suggested to be associated with OCD. However, there is no study reporting that COMT activity is decreased in OCD patients and that the decrease is mediated by the V158M polymorphism. Therefore, the purpose of our study was to assess COMT activity in OCD by measuring plasma levels of 3-O-methyl-dopa (3-OMD), which result from the methylation of levodopa by COMT, and to investigate the relationship between 3-OMD levels and the V158M polymorphism. We also examined whether 3-OMD levels represented an endophenotype, associated with the genetic liability to OCD, by assessing unaffected relatives of OCD patients. We assessed plasma 3-OMD levels in a sample of drug-free OCD probands (n = 34) and their unaffected parents (n = 63), and compared them with controls (n = 85). The COMT V158M polymorphism was genotyped in all participants. Lower plasma 3-OMD levels were found in OCD probands and their unaffected parents compared to controls. The COMT M158 allele was associated with reduced plasma 3-OMD levels in a co-dominant manner, both in OCD probands and their relatives, but not in controls. Our results suggest that COMT activity could act as a limiting factor for the production of 3-OMD in OCD patients and in their relatives. These findings further support a role of COMT in the susceptibility to OCD and provide evidence that 3-OMD levels could represent an endophenotype in OCD.

A Haplotype Containing Quantitative Trait Loci for SLC1A1 Gene Expression and Its Association With Obsessive-Compulsive Disorder

Recent evidence from linkage analyses and follow-up candidate gene studies supports the involvement of SLC1A1, which encodes the neuronal glutamate transporter, in the development of obsessive-compulsive disorder (OCD). To determine the role of genetic variation of SLC1A1 in OCD in a large case-control study and to better understand how SLC1A1 variation affects functionality. A case-control study. Publicly accessible SLC1A1 expression and genotype data. Three hundred twenty-five OCD probands and 662 ethnically and sex-matched controls. Probands were assessed with the Structured Clinical Interview for DSM-IV, the Yale-Brown Obsessive Compulsive Scale, and the Saving Inventory-Revised. Six single-nucleotide polymorphisms (SNPs) were genotyped. Multiple testing corrections for single-marker and haplotype analyses were performed by permutation. Gene expression of SLC1A1 is heritable in lymphoblastoid cell lines. We identified 3 SNPs in or near SLC1A1 that correlated with gene expression levels, 1 of which had previously been associated with OCD. Two of these SNPs also predicted expression levels in human brain tissue, and 1 SNP was further functional in reporter gene studies. Two haplotypes at 3 SNPs, rs3087879, rs301430, and rs7858819, were significantly associated with OCD after multiple-testing correction and contained 2 SNPs associated with expression levels. In addition, another SNP correlating with SLC1A1 gene expression, rs3933331, was associated with an OCD-hoarding subphenotype as assessed by 2 independent, validated scales. Our case-control data corroborate previous smaller family-based studies that indicated that SLC1A1 is a susceptibility locus for OCD. The expression and genotype database-mining approach we used provides a potentially useful complementary approach to strengthen future candidate gene studies in neuropsychiatric and other disorders.

Cognitive endophenotypes in OCD: A study of unaffected siblings of probands with familial OCD

Background Impairments in executive functions and non-verbal memory are considered potential endophenotype markers of obsessive–compulsive disorder (OCD). For the neuropsychological deficits to be considered endophenotypes, they should be demonstrable in unaffected family members. Aim To compare the neuropsychological performance in unaffected siblings of probands with familial OCD with that of individually matched healthy controls. Methods Twenty-five unaffected siblings of OCD probands with familial OCD, and 25 individually matched healthy controls were assessed with tests of attention, executive function, memory and intelligence. Results Unaffected siblings showed significant deficits in tests of decision making and behavioural reversal i.e., the Iowa Gambling Task (IGT) and the Delayed Alternation Test (DAT) respectively, but performed adequately in other tests. Conclusions Our study suggests that the deficits in decision making and behavioural reversal could be potential endophenotypes in OCD. These deficits are consistent with the proposed neurobiological model of OCD involving the orbitofrontal cortex. Future studies could couple cognitive and imaging strategies to identify neurocognitive endophenotypes in homogenous samples of OCD.

Predicting genetic loading from symptom patterns in obsessive- compulsive disorder: a latent variable analysis

Some symptom dimensions in obsessive-compulsive disorder (OCD) patients have a familial and putative genetic foundation, based on replicated findings in studies of sib-pairs with OCD. However, these symptom dimensions are all from exploratory factor analyses of Yale-Brown Obsessive-Compulsive Scale Symptom Checklist ratings based on non-empirically derived symptom categories, rather than individual symptoms. In this study, we used a novel latent variable mixture model analysis to identify meaningful patient subgroupings. This was preceded by a confirmatory factor analysis of a 65-item OCD symptom inventory from 398 OCD probands, which yielded a five-factor solution. Data from all five symptom factors were used in a latent variable mixture model analysis, which identified two statistically separate OCD subpopulations. One group of probands had a significantly higher proportion of OCD-affected afflicted relatives (parents or close parental relatives), whereas the other group had a less prevalent familial OCD. The group with the more familial OCD was also found to have an earlier age of OCD onset, more severe OCD symptoms, and greater psychiatric comorbidity and impairment. Especially if the results are verified in other samples, this research paradigm, which identified characteristics of individuals with familial OCD, should prove useful in carrying out genome-wide linkage and association studies of OCD and may provide a model for other symptom-based studies of additional medical disorders.