The Relationship Between Polygenic Risk Scores and Cognition in Schizophrenia.

Background: Cognitive impairment is a clinically important feature of schizophrenia. Polygenic risk score (PRS) methods have demonstrated genetic overlap between schizophrenia, bipolar disorder (BD), major depressive disorder (MDD), educational attainment (EA), and IQ, but very few studies have examined associations between these PRS and cognitive phenotypes within schizophrenia cases.

Methods: We combined genetic and cognitive data in 3034 schizophrenia cases from 11 samples using the general intelligence factor g as the primary measure of cognition.

Error-related brain activity as a transdiagnostic endophenotype for obsessive-compulsive disorder, anxiety and substance use disorder.

Background: Increased neural error-signals have been observed in obsessive-compulsive disorder (OCD), anxiety disorders, and inconsistently in depression. Reduced neural error-signals have been observed in substance use disorders (SUD). Thus, alterations in error-monitoring are proposed as a transdiagnostic endophenotype.

Impaired Antisaccades in Obsessive-Compulsive Disorder: Evidence From Meta-Analysis and a Large Empirical Study.

Increasing evidence indicates that patients with obsessive-compulsive disorder (OCD) exhibit alterations in fronto-striatal circuitry. Performance deficits in the antisaccade task would support this model, but results from previous small-scale studies have been inconclusive as either increased error rates, prolonged antisaccade latencies, both or neither have been reported in OCD patients. In order to address this issue, we investigated antisaccade performance in a large sample of OCD patients ( = 169) and matched control subjects ( = 183).

Schizotypy and smooth pursuit eye movements as potential endophenotypes of obsessive-compulsive disorder.

Patients with obsessive-compulsive disorder (OCD) show dysfunctions of the fronto-striatal circuitry, which imply corresponding oculomotor deficits including smooth pursuit eye movements (SPEM). However, evidence for a deficit in SPEM is inconclusive, with some studies reporting reduced velocity gain while others did not find any SPEM dysfunctions in OCD patients. Interestingly, psychosis-like traits have repeatedly been linked to both OCD and impaired SPEM.

Neural correlates of working memory deficits and associations to response inhibition in obsessive compulsive disorder.

Previous research in patients with obsessive-compulsive disorder (OCD) has indicated performance decrements in working memory (WM) and response inhibition. However, underlying neural mechanisms of WM deficits are not well understood to date, and empirical evidence for a proposed conceptual link to inhibition deficits is missing. We investigated WM performance in a numeric n-back task with four WM load conditions during functional Magnetic Resonance Imaging (fMRI) in 51 patients with OCD and 49 healthy control participants who were matched for age, sex, and education.

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.

Neurocognitive functioning in parents of schizophrenia patients: Attentional and executive performance vary with genetic loading.

Neuropsychological deficits are candidate endophenotypes of schizophrenia which can assist to explain the neurocognitive impact of genetic risk variants. The identification of endophenotypes is often based on the familiality of these phenotypes. Several studies demonstrate neuropsychological deficits in unaffected biological relatives of schizophrenia patients without differentiating between genetic and non-genetic factors underlying these deficits.

Replication of the association between CHRNA4 rs1044396 and harm avoidance in a large population-based sample.

Harm avoidance is a personality trait characterized by excessive worrying and fear of uncertainty, which has repeatedly been related to anxiety disorders. Converging lines of research in rodents and humans point towards an involvement of the nicotinic cholinergic system in the modulation of anxiety. Most notably, the rs1044396 polymorphism in the CHRNA4 gene, which codes for the α4 subunit of the nicotinic acetylcholine receptor, has been linked to negative emotionality traits including harm avoidance in a recent study.

Smaller than expected cognitive deficits in schizophrenia patients from the population-representative ABC catchment cohort.

Most neuropsychological studies on schizophrenia suffer from sample selection bias, with male and chronic patients being overrepresented. This probably leads to an overestimation of cognitive impairments. The present study aimed to provide a less biased estimate of cognitive functions in schizophrenia using a population-representative catchment area sample.

Cross-disorder genome-wide analyses suggest a complex genetic relationship between Tourette's syndrome and OCD.

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.

Copy number variation in obsessive-compulsive disorder and tourette syndrome: a cross-disorder study.

Objective: Obsessive-compulsive disorder (OCD) and Tourette syndrome (TS) are heritable neurodevelopmental disorders with a partially shared genetic etiology. This study represents the first genome-wide investigation of large (>500 kb), rare (<1%) copy number variants (CNVs) in OCD and the largest genome-wide CNV analysis in TS to date.

Method: The primary analyses used a cross-disorder design for 2,699 case patients (1,613 ascertained for OCD, 1,086 ascertained for TS) and 1,789 controls.

Partitioning the heritability of Tourette syndrome and obsessive compulsive disorder reveals differences in genetic architecture.

The direct estimation of heritability from genome-wide common variant data as implemented in the program Genome-wide Complex Trait Analysis (GCTA) has provided a means to quantify heritability attributable to all interrogated variants. We have quantified the variance in liability to disease explained by all SNPs for two phenotypically-related neurobehavioral disorders, obsessive-compulsive disorder (OCD) and Tourette Syndrome (TS), using GCTA. Our analysis yielded a heritability point estimate of 0.

Characterization of SLITRK1 variation in obsessive-compulsive disorder.

Obsessive compulsive disorder (OCD) is a syndrome characterized by recurrent and intrusive thoughts and ritualistic behaviors or mental acts that a person feels compelled to perform. Twin studies, family studies, and segregation analyses provide compelling evidence that OCD has a strong genetic component. The SLITRK1 gene encodes a developmentally regulated stimulator of neurite outgrowth and previous studies have implicated rare variants in this gene in disorders in the OC spectrum, specifically Tourette syndrome (TS) and trichotillomania (TTM).

5-HT3 receptor influences the washing phenotype and visual organization in obsessive-compulsive disorder supporting 5-HT3 receptor antagonists as novel treatment option.

A role of the HTR3A-E genes in obsessive-compulsive disorder (OCD) can be expected based on promising effects of 5-HT3 receptor antagonists as adjunctive treatment of OCD. We therefore genotyped six common coding or promoter variants within the HTR3A-E genes in a case-control-sample consisting of N=236 OCD patients and N=310 control subjects and in N=58 parent-child-trios. Given the heterogeneous OCD phenotype, we also investigated OCD symptom dimensions and cognitive endophenotypes in subsamples.

The functional coding variant Asn107Ile of the neuropeptide S receptor gene (NPSR1) influences age at onset of obsessive-compulsive disorder.

Neuropeptide S (NPS) is a novel central acting neuropeptide that modulates several brain functions. NPS has shown strong anxiolytic-like effects and interactions with other central transmitter systems, including serotonin and glutamate. A coding variation (Asn107Ile) of the NPS receptor gene (NPSR1) was associated with panic disorder and schizophrenia.

Nicotine enhances antisaccade performance in schizophrenia patients and healthy controls.

Nicotine has been proposed to be a cognitive enhancer, particularly in schizophrenia patients. So far, the published studies of nicotine effects on antisaccade performance in schizophrenia patients only tested participants who were deprived smokers. Thus, we aimed to test both smoking and non-smoking patients as well as healthy controls in order to extend previous findings.

Association of amygdala volumes with cortisol secretion in unipolar depressed patients.

Major depressive disorder (MDD) is accompanied by morphological changes of brain structures which are of great importance in the neural circuitry mediating depression like the hippocampus and the amygdala. Hyperactivity of the hypothalamic-pituitary-adrenocortical (HPA) system resulting in enhanced glucocorticoid secretion can often be observed during depression and has been thought to play an important role in inducing these morphological changes. We used magnetic resonance imaging to investigate alterations of amygdala and hippocampal volumes in 86 in-patients with unipolar depression and 87 healthy controls, and we then correlated amygdala and hippocampal volumes of 76 in-patients with the area under the curve of cortisol secretion in the dexamethasone/corticotropin releasing hormone (Dex/CRH) test at baseline and during short-term antidepressant therapy.

Investigation of tryptophan hydroxylase 2 (TPH2) in schizophrenia and in the response to antipsychotics.

Serotonergic transmission is considered relevant in the pathophysiology and the treatment of schizophrenia. Tryptophan hydroxylase (TPH) is the rate limiting enzyme in the biosynthesis of serotonin. While the TPH1 gene has been found to be associated with schizophrenia, studies focusing on TPH2 variants did not yield conclusive results for schizophrenia or the response to antipsychotic medication.

A variant of the neuronal amino acid transporter SLC6A15 is associated with ACTH and cortisol responses and cognitive performance in unipolar depression.

Major depressive disorder (MDD) is accompanied by both cognitive impairments and a hyperactivity of the hypothalamic-pituitary-adrenocortical (HPA) system, resulting in an enhanced glucocorticoid secretion. Cortisol acts via mineralocorticoid and glucocorticoid receptors densely located in the hippocampus, a brain area that is important regarding cognitive functions and especially memory functions. Recently, a variant (rs1545843) affecting transcription of the human SLC6A15 gene has been associated with depression in a genome-wide association study.

Schizophrenia risk polymorphisms in the TCF4 gene interact with smoking in the modulation of auditory sensory gating.

Several polymorphisms of the transcription factor 4 (TCF4) have been shown to increase the risk for schizophrenia, particularly TCF4 rs9960767. This polymorphism is associated with impaired sensorimotor gating measured by prepulse inhibition--an established endophenotype of schizophrenia. We therefore investigated whether TCF4 polymorphisms also affect another proposed endophenotype of schizophrenia, namely sensory gating assessed by P50 suppression of the auditory evoked potential.

Antisaccade performance in patients with obsessive-compulsive disorder and unaffected relatives: further evidence for impaired response inhibition as a candidate endophenotype.

Cognitive dysfunctions such as inhibitory deficits and visuospatial abnormalities are often found in patients with obsessive-compulsive disorder (OCD). Recent findings in unaffected relatives indicate that response inhibition and other neuropsychological functions may also constitute endophenotypes of OCD. In the present study, 30 OCD patients, 30 first-degree relatives, and 30 healthy control subjects were assessed using a comprehensive neuropsychological test battery.

The functional coding variant Asn107Ile of the neuropeptide S receptor gene (NPSR1) is associated with schizophrenia and modulates verbal memory and the acoustic startle response.

Recently, the neuropeptide S (NPS) neurotransmitter system has been identified as a promising psychopharmacological drug target given that NPS has shown anxiolytic-like and stress-reducing properties and memory-enhancing effects in rodent models. NPS binds to the G-protein-coupled receptor encoded by the neuropeptide S receptor gene (NPSR1). A functional variant within this gene leads to an amino-acid exchange (rs324981, Asn107Ile) resulting in a gain-of-function in the Ile107 variant which was recently associated with panic disorder in two independent studies.

Impact of TCF4 on the genetics of schizophrenia.

Mutations of the transcription factor 4 (TCF4) gene cause mental retardation with or without associated facial dysmorphisms and intermittent hyperventilation. Subsequently, a polymorphism of TCF4 was shown in a genome-wide association study to slightly increase the risk of schizophrenia. We have further analysed the impact of this TCF4 variant rs9960767 on early information processing and cognitive functions in schizophrenia patients.

A promoter variant of SHANK1 affects auditory working memory in schizophrenia patients and in subjects clinically at risk for psychosis.

Mutations in postsynaptic scaffolding genes contribute to autism, thus suggesting a role in pathological processes in neurodevelopment. Recently, two de novo mutations in SHANK3 were described in schizophrenia patients. In most cases, abnormal SHANK3 genotype was also accompanied by cognitive disruptions.