Additional evidence that genetic variation of MAO‐A gene supports a gender subtype in obsessive‐compulsive disorder

Studies have recently reported a sexually dimorphic association between obsessive‐compulsive disorder (OCD) and a polymorphism related with variations in MAO‐A activity. These observations suggest the possibility of gender differences in genetic susceptibility for OCD. We thus reexamined the MAO‐A/EcoRV polymorphism in a sample of 122 OCD patients and 124 healthy subjects. An excess of allele 1 in OCD females with major depression disorder was confirmed as previously reported. This difference was more strongly associated with OCD females than males in the total sample. Finally, we analyzed a sample of 51 OCD trios. Haplotype‐based haplotype relative risk (HHRR) analysis of the inheritance of the MAO‐A variants revealed in the female probands that 14 out of 19 transmitted the allele 1, providing significant evidence for an allelic association between OCD and MAO‐A gene. In conclusion, our findings may provide molecular evidence to identify a clinically meaningful gender subtype. However, an effort should be made to replicate the analysis in larger samples of informative parents using strategies such as transmission disequilibrium test to allow definite conclusions. © 2001 Wiley‐Liss, Inc.     

Volitional saccade performance in a large sample of patients with obsessive‐compulsive disorder and unaffected first‐degree relatives

Recent evidence indicates that patients with obsessive‐compulsive disorder (OCD) as well as their unaffected first‐degree relatives show deficits in the volitional control of saccades, suggesting that volitional saccade performance may constitute an endophenotype of OCD. Here, we aimed to replicate and extend these findings in a large, independent sample. One hundred and fifteen patients with OCD, 103 healthy comparison subjects without a family history of OCD, and 31 unaffected first‐degree relatives of OCD patients were examined using structured clinical interviews and performed a volitional saccade task as well as a prosaccade task. In contrast to previous reports, neither patients nor relatives showed impairments in the performance of volitional saccades compared to healthy controls. Notably, medicated patients did not differ from nonmedicated patients, and there was no effect of depressive comorbidity. Additional analyses investigating correlations between saccade performance and OCD symptom dimensions yielded no significant associations. In conclusion, the present results do not support the notion that volitional saccade execution constitutes an endophenotype of OCD. Possible explanations for inconsistencies with previous studies are discussed.     

Thought‐action fusion and inflated responsibility beliefs in obsessive‐compulsive disorder

In obsessive‐compulsive disorder (OCD), inflated responsibility (IR) beliefs and thought‐action fusion (TAF) are two cognitive schema argued to contribute to obsessions and compulsions. We investigated whether IR and TAF are OCD‐specific or whether they occur in other anxiety disorders. Adults diagnosed with OCD (n = 20) or other anxiety disorders (n = 21), and non‐clinical controls (n = 22) completed measures of OCD symptomatology and severity, TAF, appraisals and interpretations of responsibility, and depression. IR was more prominent in those with OCD as compared with those with other anxiety disorders, with correlational analyses confirming that a high sense of personal responsibility was associated with high levels of obsessionality even after controlling for depression. No group differences, however, emerged between the clinical groups on measures of TAF, both groups showing elevated TAF compared with controls. Indeed, TAF and obsessional symptoms were correlated only in the presence of negative affect. These results suggest that although IR may be higher in those with OCD compared with other anxiety disorders, TAF is not specific to OCD. Results are discussed in the context of cognitive appraisal models of OCD.     

Genome‐wide linkage analysis of families with obsessive‐compulsive disorder ascertained through pediatric probands

The goal of this study was to identify chromosomal regions likely to contain susceptibility alleles for early‐onset obsessive‐compulsive disorder (OCD). A genome scan was done in 56 individuals from seven families ascertained through pediatric OCD probands; 27 of the 56 subjects had a lifetime diagnosis of definite OCD. Denser mapping of regions on chromosomes 2, 9, and 16 was subsequently done with those subjects and ten additional subjects from the largest family in the study. Direct interviews were completed with 65 of the 66 genotyped individuals. Relatives were interviewed blind to proband status. Of the 65 interviewed individuals, 32 had a lifetime diagnosis of definite OCD. Three of the seven probands had a history of Tourette disorder. Two of the 25 relatives with OCD had a tic history, whereas none of the 33 relatives without OCD had tics. The genome scan consisted of 349 microsatellite markers with an average between‐marker distance of 11.3 centiMorgan (cM). Fine mapping was done with 24 additional markers at an average spacing of 1.6 cM. Parametric and nonparametric linkage analyses were conducted using GENEHUNTER⁺. The maximum multipoint LOD score with a dominant model was 2.25 on 9p. However, with fine mapping and additional subjects, that LOD score decreased to 1.97. The maximum multipoint nonparametric LOD* score was 1.73 on 19q. The maximum multipoint LOD score with a recessive model was 1.40 on 6p. The results provide suggestive evidence for linkage on 9p and identify regions requiring further study with much larger samples. © 2002 Wiley‐Liss, Inc.     

Genetic meta‐analysis of obsessive–compulsive disorder and self‐report compulsive symptoms

We investigated whether obsessive–compulsive (OC) symptoms from a population‐based sample could be analyzed to detect genetic variants influencing obsessive–compulsive disorder (OCD). We performed a genome‐wide association studies (GWAS) on the obsession (rumination and impulsions) and compulsion (checking, washing, and ordering/precision) subscales of an abbreviated version of the Padua Inventory (N = 8,267 with genome‐wide genotyping and phenotyping). The compulsion subscale showed a substantial and significant positive genetic correlation with an OCD case–control GWAS (r _G = 0.61, p = .017) previously published by the Psychiatric Genomics Consortium (PGC‐OCD). The obsession subscale and the total Padua score showed no significant genetic correlations (r _G = ?0.02 and r _G = 0.42, respectively). A meta‐analysis of the compulsive symptoms GWAS with the PGC‐OCD revealed no genome‐wide significant Single‐Nucleotide Polymorphisms (SNPs combined N = 17,992, indicating that the power is still low for individual SNP effects). A gene‐based association analysis, however, yielded two novel genes (WDR7 and ADCK1). The top 250 genes in the gene‐based test also showed a significant increase in enrichment for psychiatric and brain‐expressed genes. S‐Predixcan testing showed that for genes expressed in hippocampus, amygdala, and caudate nucleus significance increased in the meta‐analysis with compulsive symptoms compared to the original PGC‐OCD GWAS. Thus, the inclusion of dimensional symptom data in genome‐wide association on clinical case–control GWAS of OCD may be useful to find genes for OCD if the data are based on quantitative indices of compulsive behavior. SNP‐level power increases were limited, but aggregate, gene‐level analyses showed increased enrichment for brain‐expressed genes related to psychiatric disorders, and increased association with gene expression in brain tissues with known emotional, reward processing, memory, and fear‐formation functions.     

Sex differences in the genetic architecture of obsessive–compulsive disorder

Obsessive–compulsive disorder (OCD) is a highly heritable complex phenotype that demonstrates sex differences in age of onset and clinical presentation, suggesting a possible sex difference in underlying genetic architecture. We present the first genome‐wide characterization of the sex‐specific genetic architecture of OCD, utilizing the largest set of OCD cases and controls available from the Psychiatric Genomics Consortium. We assessed evidence for several mechanisms that may contribute to sex differences including a sex‐dependent liability threshold, the presence of individual sex‐specific risk variants on the autosomes and the X chromosome, and sex‐specific pleiotropic effects. Furthermore, we tested the hypothesis that genetic heterogeneity between the sexes may obscure associations in a sex‐combined genome‐wide association study. We observed a strong genetic correlation between male and female OCD and no evidence for a sex‐dependent liability threshold model, suggesting that sex‐combined analysis does not suffer from widespread loss of power because of genetic heterogeneity between the sexes. While we did not detect any significant sex‐specific genome‐wide single nucleotide polymorphisms (SNP) associations, we did identify two significant gene‐based associations in females: GRID2 and GRP135, which showed no association in males. We observed that the SNPs with sexually differentiated effects showed an enrichment of regulatory variants influencing expression of genes in brain and immune tissues. These findings suggest that future studies with larger sample sizes hold great promise for the identification of sex‐specific genetic risk factors for OCD.     

Self‐compassion and emotion regulation difficulties in obsessive–compulsive disorder

Lack of self‐compassion and deficits in emotion regulation are associated with various psychopathological symptoms and may play a role in the development and maintenance of obsessive–compulsive disorder (OCD). However, further empirical research is still needed to better understand these constructs in the context of this disorder. The present study investigated the relation between self‐compassion, emotion regulation difficulties, obsessive beliefs, and obsessive–compulsive symptom severity in 90 patients with OCD using self‐report questionnaires. Symptom severity and obsessive beliefs were negatively correlated to self‐compassion and positively associated with emotion regulation difficulties. Additionally, self‐compassion showed a negative relation to emotion regulation difficulties. Emotion regulation difficulties—but not self‐compassion—predicted symptom severity when controlling for obsessive beliefs and depression in a hierarchical regression analysis. Further analyses showed that emotion regulation deficits mediated the relationship between self‐compassion and OCD symptom severity. Our results provide preliminary evidence that targeting self‐compassion and putting more emphasis on emotion regulation deficits might be promising treatment approaches for patients with OCD. Future studies could investigate which specific interventions that directly address these variables improve treatment outcome.     

Comparing effects of detached mindfulness and cognitive restructuring in obsessive‐compulsive disorder using ecological momentary assessment

Ecological momentary assessment (EMA) has been shown to be a valid and sensitive measure of treatment effects in obsessive‐compulsive disorder (OCD). As part of a clinical trial, this EMA study deals with a comparison of two treatment conditions, that is, cognitive restructuring (CR) and detached mindfulness (DM). EMA data from n = 39 OCD patients were available from a randomized clinical trial on the effectiveness of CR and DM. Smartphone‐based EMA sampling spread over 4 days each before and after treatment, with 10 random prompts per day and a 2‐week intervention of either CR or DM. We tracked CR strategies (e.g., questioning an appraisal by re‐evaluating risk), DM strategies (e.g., allowing one's thoughts to come and go), and application of newly learned strategies during Post‐Treatment EMA. Although there was a trend towards DM strategies being applied more often during Pre‐Treatment EMA than CR strategies, we did not find differences during Post‐Treatment EMA between CR and DM regarding frequency or difficulty of application and experienced relief. As expected, we found a clear pre‐post increase for all CR and DM behaviours except for one DM item. However, we did not find a treatment‐specific increase of CR and DM behaviours; that is, both interventions equally well promoted a seemingly general treatment effect. Despite the ecological validity of EMA, however, social desirability effects cannot be ruled out, so that this conclusion must be handled cautiously. Further research is needed to replicate and generalize our results.     

Exclusion of linkage between schizophrenia and the gene encoding a neutral amino acid glutamate/aspartate transporter,SLC1A5

An abnormality in glutamatergic function has been hypothesized as being of etiological importance in schizophrenia. Twenty-three multiplex English and Icelandic schizophrenia families were genotyped with a polymorphic dinucleotide repeat sequence in the 3′-untranslated region of the glutamate/aspartate transporter gene called SLC1A5. Using the lod and a model-free method of linkage analysis (MFLINK), no evidence of linkage between SLC1A5 and schizophrenia was found. Our results do not support the hypothesis that SLC1A5 gene mutations or allelic variants provide a major gene contribution to the etiology of schizophrenia. However, because of the likelihood of heterogeneity of linkage in schizophrenia, there is a case for testing other pedigrees for linkage to the SLC1A5 locus. The SLC1A5 locus is one of a complex family of genes encoding neutral amino acid transporter proteins and the genetic relation between these other loci and schizophrenia has not yet been established. Am. J. Med. Genet. 74:50–52, 1997. © 1997 Wiley-Liss, Inc.     

The erring brain: Error‐related negativity as an endophenotype for OCD—A review and meta‐analysis

Obsessive‐compulsive disorder (OCD) is a complex and heterogeneous disorder that is associated with high personal and societal costs. Feelings of doubt, worry, and repetitive behavior, key symptoms of OCD, have been linked to hyperactive error signals in the brain. The error‐related negativity (ERN) represents a validated marker of error processing in the ERP. Increased ERN amplitudes in OCD have been reported very robustly over the last 20 years. This article integrates results from 38 studies analyzing the ERN in OCD, using a quantitative meta‐analysis. Meta‐regressions were used to examine potential moderators such as task type, symptom severity, age, and sample size. The meta‐analysis reveals a robust increase of ERN in OCD patients compared to healthy participants in response‐conflict tasks (SMD ?0.55) that is not modulated by symptom severity and age. No increase in ERN in OCD was observed in tasks that do not induce response conflict (SMD ?0.10). In addition to the meta‐analysis, the current article reviews evidence supporting that increased ERN amplitudes in OCD fulfill central criteria for an endophenotype. Further, the specificity of increased ERN amplitudes for OCD and its suitability as a potential transdiagnostic endophenotype is discussed. Finally, the clinical utility and clinical applications are examined. Overall, the evidence that increased ERN amplitudes represent a promising endophenotype indicating vulnerability for OCD is compelling. Furthermore, alterations in ERN are not limited to OCD and may constitute a transdiagnostic endophenotype. Altered neural error signals might serve as a diagnostic or predictive marker and represent a promising target for interventions.     

Identification of novel SLC3A1 gene mutations in Spanish cystinuria families and association with clinical phenotypes

Cystinuria is an inherited metabolic disease characterized by an abnormal urinary excretion of cystine and dibasic amino acids, leading to kidney stone formation. Incidence of cystinuria in the Mediterranean Spanish population is one of the highest in the world. In view of the low prevalence of previously reported mutations in the SLC3A1 gene, analyses to identify novel variants were carried out on 20 cystinuria families. Additionally, we investigated the possible association between these molecular variants and clinical phenotypes. Genomic DNA from 48 cystinuria patients, 44 healthy relatives and 81 unrelated controls from the East Mediterranean coast of Spain was screened by conformation sensitive gel electrophoresis. Abnormal patterns were confirmed by nucleotide sequence determination and by further restriction fragment-length polymorphism. We only found 11 genetic variants within the SLC3A1 gene: five known polymorphisms (114C > A, 231T > A, 1136 + 3delT, 1332 + 7T > C and 1338G > A), four point mutations (M467T, R452W, I105R and Y461X), one single base pair deletion (1767delA) and one 2-bp insertion (1670insAT). Two of these genetic variants (I105R and 1670insAT) were described for the first time. All mutations but one were detected in families classified as Type I cystinuria due to the transmission pattern of the disease. Association analyses revealed that 231T > A (M467T), 1136 + 3delT and 1332 + 7T > C genetic variants were statistically related with urinary amino acid excretion in cystinuria patients. Although some molecular variants within the SLC3A1 gene were associated with clinical traits in cystinuria patients, the low detection rate of mutations in this gene strongly suggests that variation of the SLC3A1 is not the major genetic factor contributing to cystinuria in this Mediterranean population.