Margaret A. Richter

Serotonin Transporter Promoter Gain-of-Function Genotypes Are Linked to Obsessive-Compulsive Disorder

A functional serotonin transporter promoter polymorphism, HTTLPR, alters the risk of disease as well as brain morphometry and function. Here, we show that HTTLPR is functionally triallelic. The L(G) allele, which is the L allele with a common G substitution, creates a functional AP2 transcription-factor binding site. Expression assays in 62 lymphoblastoid cell lines representing the six genotypes and in transfected raphe-derived cells showed codominant allele action and low, nearly equivalent expression for the S and L(G) alleles, accounting for more variation in HTT expression than previously recognized. The gain-of-function L(A)L(A) genotype was approximately twice as common in 169 whites with obsessive-compulsive disorder (OCD) than in 253 ethnically matched controls. We performed a replication study in 175 trios consisting of probands with OCD and their parents. The L(A) allele was twofold overtransmitted to the patients with OCD. The HTTLPR L(A)L(A) genotype exerts a moderate (1.8-fold) effect on risk of OCD, which crystallizes the evidence that the HTT gene has a role in OCD.

Association of a glutamate (NMDA) subunit receptor gene (GRIN2B) with obsessive-compulsive disorder: a preliminary study.

RationaleRecent investigation suggests that a reversible glutamatergically mediated thalamocortical-striatal dysfunction may serve as a reliable pathophysiological and treatment response marker for obsessive-compulsive disorder (OCD). We postulated that N-methyl-d-aspartate (NMDA) receptors were involved in OCD, and specifically that polymorphisms in the 3′ untranslated region of GRIN2B (glutamate receptor, ionotropic, N-methyl-d-aspartate 2B) were associated with OCD in affected families.ObjectivesThe objective of this investigation was to test the association between GRIN2B variants and transmission of the OCD trait using a family-based design.MethodsUsing the Family Based Association Test (FBAT), we tested for association with OCD diagnosis in 130 families, and also performed a haplotype analysis. FBAT was additionally used in a subset of 98 families to test for association with the quantitative phenotype of lifetime OCD symptom severity.ResultsUnder a non-additive model of inheritance, the 5072T/G variant was significantly associated with OCD even after correcting for the number of models tested (P=0.014). In addition, there was a significant positive association with OCD diagnosis (P=0.002) for the 5072G–5988T haplotype under the recessive model.ConclusionsAlthough preliminary and requiring replication in larger samples, these results provide evidence that GRIN2B may be associated with susceptibility to OCD. Coupled with basic neuroscience and clinical neuroimaging findings in patients with OCD, our results provide new and converging support for the role of altered glutamatergic neurotransmission in the pathogenesis of OCD.

Obsessive compulsive disorder, response to serotonin reuptake inhibitors and the serotonin transporter gene

Obsessive compulsive disorder (OCD) is a common illness, characterized by anxiety- provoking thoughts and the need to perform rituals. OCD is most commonly treated with a class of pharmacological agents known as serotonin reuptake inhibitors (SRIs). SRIs block the reuptake of serotonin (5-HT) into the presynaptic neuron, a process mediated by the serotonin transporter (5-HTT). The successful use of SRIs in OCD has led to the hypothesis that 5-HTT may play a pivotal role in the pathogenesis of OCD. We decided to study this hypothesis from a genetic perspective, because family and twin studies suggest that there is a strong genetic component to OCD. In addition, the sequence of the gene for 5-HTT is available, and a 44-bp insertion/deletion polymorphism has been detected in the promoter region of the gene. There is evidence that this polymorphism alters expression of the transporter protein. We typed 72 OCD patients and 72 matched controls, and found no statistically significant difference between the two groups (χ2 = 4.319, P = 0.115, 2 d.f.). We observed however a trend towards increased homozygosity in the patient group. We also rated (retrospectively) the patients’ clinical responses to SRIs. No association was observed between these ratings and the promoter region polymorphism in the serotonin transporter gene. Given the pharmacological evidence favoring a role for 5-HTT in OCD and SRI response, further genetic evaluation of the serotonin transporter in OCD is indicated.

Memory and confidence in memory judgments among individuals with obsessive compulsive disorder and non-clinical controls

The present study investigated episodic memory functioning in: (1) obsessive compulsive disorder (OCD) patients with primarily checking symptoms (i.e. checkers); (2) OCD patients without checking symptoms (i.e. non-checkers); and (3) non-clinical control participants. On a measure of recall, all groups were statistically equivalent with respect to the proportion of words correctly recalled. Using a recognition measure, checkers were unimpaired in episodic memory, as compared to non-checkers and non-clinical controls. However, relative to the other groups, patients with checking symptoms showed decreased confidence in their correct and incorrect recognition memory judgements, according to their item-by-item self-report confidence ratings. When checkers correctly identified previously seen words, they were also slower to respond than were the other groups, supporting the view that they were less confident in their memory judgments relative to the other groups, which did not differ on this measure. The results of the present study suggest that OCD checking is not related to memory impairments per se but rather that checking in OCD is a symptom of decreased confidence in memory.

Quality of Life in OCD: Differential Impact of Obsessions, Compulsions, and Depression Comorbidity

Objective: An anxiety disorder severely affects the sufferers quality of life (QOL), and this may be particularly true of those with obsessive–compulsive disorder (OCD). This study examines the differential impact of obsessions, compulsions, and depression comorbidity on the QOL of individuals with OCD. Method: Forty-three individuals diagnosed with OCD according to DSM-IV criteria and experiencing clinically significant obsessions and compulsions completed measures of QOL, obsessive–compulsive symptom severity, and depression severity. Results: Obsession severity was found to significantly predict patient QOL, whereas the severity of compulsive rituals did not impact on QOL ratings. Comorbid depression severity was the single greatest predictor of poor QOL, accounting for 54% of the variance. Conclusions: Given the importance of these symptoms, treatments that directly target obsessions and secondary depression symptoms in OCD are warranted. However, replication of these findings in a prospective cohort study is required, because although the the current studys cross-sectional design allows for the examination of the associations among obsessions, depression, and QOL, it cannot establish their temporal framework (that is, causal relations).

Investigation of dopamine system genes in obsessive-compulsive disorder.

Evidence from anatomical, pharmacological, and animal studies on the involvement of the dopamine system in obsessive-compulsive disorder (OCD) is mounting. This, along with evidence for a genetic diathesis provided by family and twin studies, prompted us to conduct genetic association studies of dopamine system genes in OCD. We genotyped OCD patients (n > 100) and matched controls for four loci: (1) a 40-base-pair repeat in the dopamine transporter gene; (2) the Taq1A polymorphism and the serine/cysteine variation in the D2 dopamine receptor gene; (3) an MscI polymorphism in the D3 dopamine receptor gene; and (4) a 48-base-pair repeat in the D4 dopamine receptor gene. Significant differences in allele frequencies were found between patients and controls for the D4 receptor gene, although replication is required with family-based controls before any conclusions can be entertained. This study represents the first comprehensive assessment of the roles of dopamine system genes in OCD.

5HT1Dβ Receptor gene implicated in the pathogenesis of Obsessive-Compulsive Disorder: further evidence from a family-based association study

Obsessive-Compulsive Disorder (OCD) is a psychiatric condition with strong evidence for a genetic component and for the involvement of genes of the serotonin system. In a recent family-based association study we reported an association between the G allele of the G861C polymorphism of the 5HT1Dβ receptor gene and OCD. The aim of the present study was to further investigate for the presence of linkage disequilibrium between each of two polymorphisms of the 5HT1Dβ receptor gene and OCD in a larger sample of OCD families. In a total of 121 families the G861C and the T371G polymorphisms of the 5HT1Dβ receptor gene were genotyped using standard protocols. The genotyping data were analyzed with a new extension of the Transmission Disequilibrium Test (FBAT). The phenotypes considered in the analyses were the diagnosis of OCD and two quantitative phenotypes related to the diagnosis and clinically relevant, ie, the age at onset and the severity of OCD symptoms. We confirmed the previously found preferential transmission of the G861 allele to the affected subjects (z = 2.262, P = 0.02). No significant association was found between the polymorphism and the quantitative phenotypes considered. These results represent a confirmation of our previous published study and thus, could have important implications for the role of the 5HT1Dβ receptor gene in the pathogenesis and treatment of OCD. Further genetic investigations on this marker considering additional polymorphisms and other quantitative phenotypes related to OCD are warranted.

Obsessive-compulsive disorder and the five-factor model of personality: distinction and overlap with major depressive disorder.

Research on individual differences in obsessive-compulsive disorder (OCD) has focused largely on analogue models with participants experiencing sub-clinical obsessions and/or compulsions. Few studies have examined the association between normal, dimensional personality traits and obsessive-compulsive symptomatology in a clinical sample. The purpose of this study was to examine personality differences in patients with a primary diagnosis of OCD (n = 98) or major depression (n = 98) using the domains and facets of the five-factor model of personality (FFM). Patients completed the self-report version of the Revised NEO Personality Inventory (NEO PI-R). When contrasted with community controls (Revised NEO Personality Inventory (NEO-PI-R) and NEO Five-Factor Inventory (NEO-FFI) professional manual, Psychological Assessment Resources, Odessa, FL, 1992), participants with OCD were found to differ across the domains (and facets) of neuroticism, extraversion, and conscientiousness and the facets of openness and agreeableness. Further, when compared to depressed participants, those with OCD were found to be more extraverted, agreeable, conscientious and less neurotic. With the exception of the conscientiousness domain (and facets), these significant differences were maintained even after controlling for depression severity. These results highlight the unique associations between trait domains and facets of the FFM and OCD.

Glutamate receptor gene (GRIN2B) associated with reduced anterior cingulate glutamatergic concentration in pediatric obsessive-compulsive disorder

In this preliminary study, 16 psychotropic-naïve pediatric patients with obsessive-compulsive disorder (OCD) were studied using magnetic resonance spectroscopy (MRS) and genotyped for six candidate polymorphisms in two glutamate system genes. A significant association was identified between the rs1019385 polymorphism of the glutamate receptor, ionotropic, N-methyl-d-aspartate 2B (GRIN2B) and decreased anterior cingulate cortex (ACC) glutamatergic concentration (Glx) but not with occipital Glx. These results suggest that GRIN2B may be associated with Glx in the ACC, a region consistently implicated in OCD.

Impulsivity in obsessive-compulsive disorder : comparisons with other anxiety disorders and within tic-related subgroups

Abstract This study investigated the relationship between impulsivity and obsessive-compulsive disorder (OCD). The Barratt Impulsiveness Scale (BIS) was used to examine (i) levels of impulsivity in individuals with OCD, panic disorder, and social phobia, as well as in nonclinical controls, and (ii) the relationship between tics and impulsivity in patients with OCD. Patients in all anxiety disorder groups reported higher levels of impulsiveness than controls, with no differences among clinical groups. OCD patients with tics reported higher levels of impulsiveness than those without tics, primarily due to elevations on the cognitive impulsiveness subscale—a finding that was related to increased severity of obsessions in the tic group. These findings do not support a clear relationship between impulsivity and OCD, but point to possible confusion between state versus trait impulsivity in the OCD literature, as well as threats to interpretability posed by overlapping criteria for symptoms and traits.