Risk For Schizophrenia Research Articles

Exposure to green spaces and schizophrenia: a systematic review.

The mental health benefits of exposure to green spaces are well known. This systematic review summarizes the evidence of green space exposure for people with schizophrenia spectrum disorders (SSDs), focusing on incidence and mental health outcomes, including mental health symptoms and health service use. The study was pre-registered (PROSPERO ID: CRD42023431954), and conducted according to PRISMA guidelines. Seven databases, reference lists, and gray literature sources were searched. Methodological quality was assessed using The Quality Assessment Tool for Quantitative Studies. 126 studies were screened, and 12 studies were eligible for inclusion. Seven studies found that exposure to green space was associated with a reduced risk of schizophrenia (lowest to highest green space exposure: HRs = 0.62-0.37; IRRs = 1.52-1.18), with five studies reporting a dose-response relationship. Of these studies, four examined childhood exposure and the remainder examined adult exposure. Regarding health service use, proximity to green space was not significantly associated with length of hospital admission, though greater green space exposure was associated with reduced hospital admission rates. Three studies found reduced symptoms of anxiety (d = -0.70-2.42), depression (d = -0.97-1.70) and psychosis (d = -0.94) with greater green space exposure. Exposure to green space reduces the risk of schizophrenia, and there is emerging evidence of the potential benefits of green space for reducing symptoms and health service use among people with SSDs. Future research using experimental and longitudinal designs will provide more robust evidence of the benefits of green space for people with SSDs.

A conserved cell-type gradient across the human mediodorsal and paraventricular thalamus.

The mediodorsal thalamus (MD) and adjacent midline nuclei are important for cognition and mental illness, but their cellular composition is not well defined. Using single-nucleus and spatial transcriptomics, we identified a conserved excitatory neuron gradient, with distinct spatial mapping of individual clusters. One end of the gradient was expanded in human MD compared to mice, which may be related to the expansion of granular prefrontal cortex in hominids. Moreover, neurons preferentially mapping onto the parvocellular division MD were associated with genetic risk for schizophrenia and bipolar disorder. Midbrain-derived inhibitory interneurons were enriched in human MD and implicated in genetic risk for major depressive disorder.

Network-wide risk convergence in gene co-expression identifies reproducible genetic hubs of schizophrenia risk

The omnigenic model posits that genetic risk for traits with complex heritability involves cumulative effects of peripheral genes on mechanistic "core genes," suggesting that in a network of genes, those closer to clusters including core genes should have higher GWAS signals. In gene co-expression networks, we confirmed that GWAS signals accumulate in genes more connected to risk-enriched gene clusters, highlighting across-network risk convergence. This was strongest in adult psychiatric disorders, especially schizophrenia (SCZ), spanning 70% of network genes, suggestive of super-polygenic architecture. In snRNA-seq cell type networks, SCZ risk convergence was strongest in L2/L3 excitatory neurons. We prioritized genes most connected to SCZ-GWAS genes, which showed robust association to a CRISPRa measure of PGC3 regulation and were consistently identified across several brain regions. Several genes, including dopamine-associated ones, were prioritized specifically in the striatum. This strategy thus retrieves current drug targets and can be used to prioritize other potential drug targets.

The schizophrenia risk gene C4 induces pathological synaptic loss by impairing AMPAR trafficking.

Neuroimmune interactions play a significant role in regulating synaptic plasticity in both the healthy and diseased brain. The complement pathway, an extracellular proteolytic cascade, exemplifies these interactions. Its activation triggers microglia-dependent synaptic elimination via the complement receptor 3 (CR3). Current models of pathological complement activity in the brain propose that accelerated synaptic loss resulting from overexpression of C4 (C4-OE), a gene associated with schizophrenia, follows this pathway. Here, we report that C4-mediated cortical hypoconnectivity is CR3-independent. Instead, C4-OE triggers impaired GluR1 trafficking through an intracellular mechanism involving the endosomal protein SNX27, resulting in pathological synaptic loss. Moreover, C4 circuit alterations in the prefrontal cortex, a brain region associated with neuropsychiatric disorders, were rescued by increasing neuronal levels of SNX27, which we identify as an interacting partner of this neuroimmune protein. Our results link excessive complement activity to an intracellular endo-lysosomal trafficking pathway altering synaptic plasticity.

Evoked Synchronization of Theta EEG Rhythm during Preparation of Memory-Guided Saccades and Antisaccaded in Normals and in Patients with Clinically High Risk for Schizophrenia

Evoked Synchronization of Theta EEG Rhythm during Preparation of Memory-Guided Saccades and Antisaccaded in Normals and in Patients with Clinically High Risk for Schizophrenia

Overexpression of the schizophrenia risk gene C4 in PV cells drives sex-dependent behavioral deficits and circuit dysfunction

Fast-spiking parvalbumin (PV)-positive cells are key players in orchestrating pyramidal neuron activity, and their dysfunction is consistently observed in myriad brain diseases. To understand how immune complement pathway dysregulation in PV cells drives disease pathogenesis, we have developed a transgenic line that permits cell-type specific overexpression of the schizophrenia-associated C4 gene. We found that overexpression of mouse C4 (mC4) in PV cells causes sex-specific alterations in anxiety-like behavior and deficits in synaptic connectivity and excitability of PFC PV cells. Using a computational model, we demonstrated that these microcircuit deficits led to hyperactivity and disrupted neural communication. Finally, pan-neuronal overexpression of mC4 failed to evoke the same deficits in behavior as PV-specific mC4 overexpression, suggesting that perturbations of this neuroimmune gene in fast-spiking neurons are especially detrimental to circuits associated with anxiety-like behavior. Together, these results provide a causative link between C4 and the vulnerability of PV cells in brain disease.

Air pollutants, genetic susceptibility and the risk of schizophrenia: large prospective study.

Evidence linking air pollutants and the risk of schizophrenia remains limited and inconsistent, and no studies have investigated the joint effect of air pollutant exposure and genetic factors on schizophrenia risk. To investigate how exposure to air pollution affects schizophrenia risk and the potential effect modification of genetic susceptibility. Our study was conducted using data on 485 288 participants from the UK Biobank. Cox proportional hazards models were used to estimate the schizophrenia risk as a function of long-term air pollution exposure presented as a time-varying variable. We also derived the schizophrenia polygenic risk score (PRS) utilising data provided by the UK Biobank, and investigated the modification effect of genetic susceptibility. During a median follow-up period of 11.9 years, 417 individuals developed schizophrenia (mean age 55.57 years, s.d. = 8.68; 45.6% female). Significant correlations were observed between long-term exposure to four air pollutants (PM2.5; PM10; nitrogen oxides, NOx; nitrogen dioxide, NO2) and the schizophrenia risk in each genetic risk group. Interactions between genetic factors and the pollutants NO2 and NOx had an effect on schizophrenia events. Compared with those with low PRS and low air pollution, participants with high PRS and high air pollution had the highest risk of incident schizophrenia (PM2.5: hazard ratio = 6.25 (95% CI 5.03-7.76); PM10: hazard ratio = 7.38 (95% CI 5.86-9.29); NO2: hazard ratio = 6.31 (95% CI 5.02-7.93); NOx: hazard ratio = 6.62 (95% CI 5.24-8.37)). Long-term exposure to air pollutants was positively related to the schizophrenia risk. Furthermore, high genetic susceptibility could increase the effect of NO2 and NOx on schizophrenia risk.

Association between the copy number variations of Methyl-CpG binding domain family and schizophrenia

Schizophrenia is recognized as one of the most severe psychiatric disorders, with its pathogenesis likely involving genetic, epigenetic, developmental, and environmental factors. Members of the Methyl-CpG Binding Domain (MBD) Family play a crucial role in the regulation of genomic DNA methylation, and studies have implicated the association between MBD family and neurodevelopmental disorders. Copy number variations (CNVs) are a significant genetic basis for human genomic variation, also playing a critical role in the genetic processes of schizophrenia. Therefore, we aimed to evaluate the susceptibility of MBD family CNVs to schizophrenia by exploring and validating them in two separate populations using CNVplex™ and qPCR methods, and to explore the relationship between MBD family CNVs and clinical phenotypes in the overall population using chi-square tests and Fisher’s exact tests. Results suggest that an increase in MBD1 gene copy number and a deficiency in MBD2 gene copy number may be associated with the risk of schizophrenia. The deficiency in MBD2 gene copy number may increase the risk of delusion of reference and delusion of persecutory in the overall sample, as well as in males. This research provides preliminary evidence supporting the association between MBD family CNVs and schizophrenia, highlighting the potential role of the MBD family in the pathogenesis of schizophrenia.

Association of GAD1 gene polymorphism rs3749034 with the information processing and cognitive event-related potentials in schizophrenia patients and healthy subjects

ObjectiveGlutamic acid decarboxylase, an enzyme in GABA biosynthesis, is encoded by the GAD1 gene, the transcriptional activity of which is affected by the rs3749034 polymorphism. The aim was to investigate the effects of rs3749034 on cognitive event-related potentials (P300) in healthy subjects and schizophrenic patients. MethodsDetermination of rs3749034 polymorphism was performed in 89 healthy volunteers and 109 schizophrenic patients (males). Two-stimulus oddball task performance and P300 auditory evoked potentials were analyzed and patient symptomatology was assessed using the Positive and Negative Syndrome Scale (PANSS). ResultsAn increased frequency of C allele carriers was disclosed in patients. In controls, superior task performance was observed in cytosine-thymine carriers, while a greater P300 amplitude and shorter latency were found in C/C carriers. Analogous effects were found in patients with a disease onset before 25 years of age. Higher N5 and lower P3 and G5 PANSS scales were revealed in C/C homozygotes. ConclusionsThe findings substantiate an involvement of GABA-ergic mechanisms in maintaining an optimal excitatory-inhibitory balance and an association of rs3749034 with early-onset disorder and negative symptoms of schizophrenia. SignificanceThese results are important for understanding underlying mechanisms and the development of evidence-based methods for assessing the risk of schizophrenia.

Recent findings and future directions for the intersection of genetic and environmental contributions to schizophrenia

It is well established that both genetic and environmental factors contribute to risk for schizophrenia (SCZ), and much progress has been made in identifying the specific factors conferring risk. However, the nature and extent of interactions between them has long been a topic of debate. Both the data and methods available to address this have evolved rapidly, enabling new prospects for identifying gene–environment interactions in SCZ. To date, there is limited evidence of strong gene–environment interactions, with environmental factors, molecular genetic risk, and family history simultaneously contributing to risk of SCZ. Still, there are several enduring challenges, some of which can likely be addressed with new tools, methods, and approaches for investigating gene–environment interplay. Consequently, advancements in this field will enhance our capacity to identify individuals most vulnerable to specific environmental exposures, which is pivotal for targeted prevention and intervention.

An observational study of auditory-evoked potential mismatch negativity response in individuals at high genetic risk for schizophrenia

Objectives: This study presents a novel approach by investigating the abnormal mismatch negativity (MMN) found during response to auditory-evoked potential (ERP) in schizophrenia (SZ) patients. Our unique focus is on the genetic high-risk (GHR) for SZ, comparing it with healthy controls (HC). In addition, we aim to illuminate the interrelationship of MMN with socio-occupational functioning in the GHR group, a novel aspect of our research. Material and Methods: We conducted this study with a rigorous methodology, ensuring the reliability and validity of our findings. Thirty first-degree relatives of SZ patients (GHR) who met the inclusion and exclusion criteria were recruited by purposive sampling and compared with thirty HCs. We collected sociodemographic and clinical data from all study participants, which were assessed by the Family Interview of Genetic Studies. GHR was evaluated for current socio-occupation functioning using the Social and Occupational Functioning Assessment Scale (SOFAS). All the participants underwent 128-channel electroencephalographic recording using an auditory-evoked responses paradigm. The MMN was calculated at the frontal electrode clusters, ensuring accurate and reliable data collection. Results: The study revealed a statistically significant difference in frontal MMN latency between GHR and HC. Moreover, a positive relationship was noted between the SOFAS score and MMN amplitude, and a negative relationship was found between the latencies at the frontal region. Conclusion: Our research has made a significant breakthrough in understanding SZ. Our findings reveal that individuals with a genetic susceptibility to SZ exhibit a unique response in a particular test known as MMN. This test measures the automatic auditory change detection mechanism, which detects minor alterations in the acoustic environment and is referred to as MMN. This newfound insight could prove instrumental in developing more effective diagnoses and treatments for SZ.

Development and initial evaluation of a clinical prediction model for risk of treatment resistance in first-episode psychosis: Schizophrenia Prediction of Resistance to Treatment (SPIRIT).

A clinical tool to estimate the risk of treatment-resistant schizophrenia (TRS) in people with first-episode psychosis (FEP) would inform early detection of TRS and overcome the delay of up to 5 years in starting TRS medication. To develop and evaluate a model that could predict the risk of TRS in routine clinical practice. We used data from two UK-based FEP cohorts (GAP and AESOP-10) to develop and internally validate a prognostic model that supports identification of patients at high-risk of TRS soon after FEP diagnosis. Using sociodemographic and clinical predictors, a model for predicting risk of TRS was developed based on penalised logistic regression, with missing data handled using multiple imputation. Internal validation was undertaken via bootstrapping, obtaining optimism-adjusted estimates of the model's performance. Interviews and focus groups with clinicians were conducted to establish clinically relevant risk thresholds and understand the acceptability and perceived utility of the model. We included seven factors in the prediction model that are predominantly assessed in clinical practice in patients with FEP. The model predicted treatment resistance among the 1081 patients with reasonable accuracy; the model's C-statistic was 0.727 (95% CI 0.723-0.732) prior to shrinkage and 0.687 after adjustment for optimism. Calibration was good (expected/observed ratio: 0.999; calibration-in-the-large: 0.000584) after adjustment for optimism. We developed and internally validated a prediction model with reasonably good predictive metrics. Clinicians, patients and carers were involved in the development process. External validation of the tool is needed followed by co-design methodology to support implementation in early intervention services.

Bayesian Rare Variant Analysis Identifies Novel Schizophrenia Putative Risk Genes.

The genetics of schizophrenia is so complex that it involves both common variants and rare variants. Rare variant association studies of schizophrenia are challenging because statistical methods for rare variant analysis are under-powered due to the rarity of rare variants. The recent Schizophrenia Exome meta-analysis (SCHEMA) consortium, the largest consortium in this field to date, has successfully identified 10 schizophrenia risk genes from ultra-rare variants by burden test, while more risk genes remain to be discovered by more powerful rare variant association test methods. In this study, we use a recently developed Bayesian rare variant association method that is powerful for detecting sparse rare risk variants that implicates 88 new candidate risk genes associated with schizophrenia from the SCHEMA case-control sample. These newly identified genes are significantly enriched in autism risk genes and GO enrichment analysis indicates that new candidate risk genes are involved in mechanosensory behavior, regulation of cell size, neuron projection morphogenesis, and plasma-membrane-bounded cell projection morphogenesis, that may provide new insights on the etiology of schizophrenia.

Brain Activation and Aberrant Effective Connectivity in the Mentalizing Network of Preadolescent Children at Familial High Risk of Schizophrenia or Bipolar Disorder

BackgroundSchizophrenia and bipolar disorder are characterized by social cognitive impairments, and recent research has identified alterations of the social brain. However, it is unknown whether familial high risk (FHR) of these disorders is associated with neurobiological alterations already present in childhood. MethodsAs part of the Danish High Risk and Resilience Study–VIA 11, we examined children at FHR of schizophrenia (n = 121, 50% female) or bipolar disorder (n = 75, 47% female) and population-based control children (PBCs) (n = 128, 48% female). Using functional magnetic resonance imaging and dynamic causal modeling, we investigated brain activation and effective connectivity during the social cognition paradigm from the Human Connectome Project. ResultsWe found similar activation of the mentalizing network across groups, including visual area V5, the dorsomedial prefrontal cortex, and the posterior superior temporal sulcus (pSTS). Nonetheless, both FHR groups showed aberrant brain connectivity in the form of increased feedforward connectivity from left V5 to pSTS compared with PBCs. Children at FHR of schizophrenia had reduced intrinsic connectivity in bilateral V5 compared with PBCs, whereas children at FHR of bipolar disorder showed increased reciprocal connectivity between the left dorsomedial prefrontal cortex and the pSTS, increased intrinsic connectivity in the right pSTS, and reduced feedforward connectivity from the right pSTS to the dorsomedial prefrontal cortex compared with PBCs. ConclusionsOur results provide first-time evidence of aberrant brain connectivity in the mentalizing network of children at FHR of schizophrenia or FHR of bipolar disorder. Longitudinal research is warranted to clarify whether aberrant brain connectivity during mentalizing constitutes an endophenotype associated with the development of a mental disorder later in life.

Non-linear development of brain morphometry in child and adolescent offspring of individuals with bipolar disorder or schizophrenia

Offspring of parents with severe mental illness (e.g., bipolar disorder or schizophrenia) are at increased risk of developing psychopathology. Structural brain alterations have been found in child and adolescent offspring of patients with bipolar disorder and schizophrenia, but the developmental trajectories of brain anatomy in this high-familial-risk population are still unclear. 300 T1-weighted scans were obtained of 187 offspring of at least one parent diagnosed with bipolar disorder (n=80) or schizophrenia (n=53) and offspring of parents without severe mental illness (n=54). The age range was 8 to 23 years old; 113 offspring underwent two scans. Global brain measures and regional cortical thickness and surface area were computed. A generalized additive mixed model was used to capture non-linear age trajectories. Offspring of parents with schizophrenia had smaller total brain volume than offspring of parents with bipolar disorder (d=-0.20, p=0.004) and control offspring (d=-0.22, p=0.005) and lower mean cortical thickness than control offspring (d=-0.23, p<0.001). Offspring of parents with schizophrenia showed differential age trajectories of mean cortical thickness and cerebral white matter volume compared with control offspring (both p’s=0.003). Regionally, offspring of parents with schizophrenia had a significantly different trajectory of cortical thickness in the middle temporal gyrus versus control offspring (p<0.001) and bipolar disorder offspring (p=0.001), which was no longer significant after correcting for mean cortical thickness. These findings suggest that particularly familial high risk of schizophrenia is related to reductions and deviating developmental trajectories of global brain structure measures, which were not driven by specific regions.

Cognitive ability, education, height and body mass index in relation to risk of schizophrenia and mortality following its diagnosis

This study examines the hypotheses that the traits of higher IQ, longer education and taller height are associated with lower risk of death as compared to traits of low IQ, short education, and short height in men with schizophrenia compared to men without schizophrenia. In total, 937,919 men born 1939-59 and 1983–1997 with information from conscription were followed for incident schizophrenia in Danish registries. Higher levels of cognitive ability, longer education, and taller height were associated with fewer cases of schizophrenia. In a sub-sample of 652,368 men with information on body mass index, underweight was associated with more and overweight and obesity were associated with fewer cases of schizophrenia compared with normal weight. Higher cognitive ability, longer education, and taller height were associated with fewer deaths from both natural and unnatural causes in both men with and without schizophrenia. Underweight was associated with more deaths from natural and unnatural causes, whereas overweight and obesity were associated with more deaths from natural causes and fewer deaths from unnatural causes in both groups of men. Due to interaction, tall height and long educational duration were associated with fewer deaths from natural causes, and obesity was associated with fewer deaths from unnatural causes among men with schizophrenia compared to men without. In conclusion, traits in young adulthood are associated with higher mortality in men with and without schizophrenia, but traits of long educational duration and obesity seem to be especially important for lower mortality in men with schizophrenia.

Association between polygenic risk for schizophrenia and retinal morphology: A cross-sectional analysis of the United Kingdom Biobank

We examined the relationship between genetic risk for schizophrenia (SZ), using polygenic risk scores (PRSs), and retinal morphological alterations. Retinal structural and vascular indices derived from optical coherence tomography (OCT) and color fundus photography (CFP) and PRSs for SZ were analyzed in N = 35,024 individuals from the prospective cohort study, United Kingdom Biobank (UKB). Results indicated that macular ganglion cell-inner plexiform layer (mGC-IPL) thickness was significantly inversely related to PRS for SZ, and this relationship was strongest within higher PRS quintiles and independent of potential confounders and age. PRS, however, was unrelated to retinal vascular characteristics, with the exception of venular tortuosity, and other retinal structural indices (macular retinal nerve fiber layer [mRNFL], inner nuclear layer [INL], cup-to-disc ratio [CDR]). Additionally, the association between greater PRS and reduced mGC-IPL thickness was only significant for participants in the 40–49 and 50–59 age groups, not those in the 60–69 age group. These findings suggest that mGC-IPL thinning is associated with a genetic predisposition to SZ and may reflect neurodevelopmental and/or neurodegenerative processes inherent to SZ. Retinal microvasculature alterations, however, may be secondary consequences of SZ and do not appear to be associated with a genetic predisposition to SZ.

Bidirectional causal associations between aging and major mental disorders: A population-based study using the two-sample mendelian randomization method from the UK biobank (AM-SRNMA 002)

AimsWhile observational studies have suggested associations linking aging and mental disorders, the question of causality has remained unclear. This study aimed to explore the causal relationship between aging level and major mental disorders. MethodsWe utilized Two-Sample Mendelian randomization (2SMR) with mental disorders data and aging indicators information from an extensive genome-wide association study (GWAS) database. The GWAS database is a comprehensive resource that compiles genetic association data, encompassing a sample size of over 450,000 individuals. We employed five methods for 2SMR and single nucleotide polymorphisms were chosen as instrumental variables. ResultsOur analyses consistently supported a bidirectional causal association between the Frailty Index (FI) and Major Depressive Disorder (MDD). Furthermore, our findings indicated potential influences, such as Attention-Deficit/Hyperactivity Disorder (ADHD) and Bipolar Disorder (BD) affecting GrimAge, and Anxiety Disorder (AD) impacting Left Hand Grip Strength (LHGS). In contrast, we observed no significant correlations for other mental disorders on FI, Telomere Length (TL), GrimAge, Appendicular Lean Mass (ALM), and LHGS. In the reverse direction, FI showed a significant impact on the risk of MDD, AD, and ADHD, while LHGS affected the risk of MDD. Importantly, no significant associations were found between other factors and the risk of MDD, BD, AD, Schizophrenia (SZ), and ADHD. ConclusionsThis 2SMR analysis has presented evidence for a bidirectional causal relationship between FI and MDD, while the relationship between ADHD, BD, and GrimAge should be more considered. Our study provides genetic evidence supporting a causal link between aging indicators and several mental illnesses.

Silver nanoparticles loaded carbon-magnetic nanocomposites: A nanozyme for colorimetric detection of dopamine

Dopamine (DA) is catecholamine neurotransmitters that play an important role in the central nervous system. In recent years people started to intentionally add DA to animal feed to enhance muscle development and increase their profit margin. Human consumption of the residual DA from animal tissues has been reported to be associated with the development of such diseases as Parkinson’s disease, epilepsy, senile dementia, and schizophrenia and pose serious human health risks. These require development of rapid, cheap, and sensitive methods for detection of DA from animal tissue. Compared to other techniques that require access to expensive instruments, skilled human power, and tiresome routine procedures, colorimetric methods provide cheap and reliable options for detection of DA. Here we report a colorimetric method based on the peroxidase-mimic activity of Fe3O4@C@AgNPs for the detection of DA. A simple wet chemical method was employed to synthesize AgNPs on hydrophilic carbon coated Fe3O4. The produced nanocomposites were characterized by transmission electron microscopy (TEM), Fourier Transform infrared spectroscopy (FTIR), and surface-enhanced Raman spectroscopy (SERS). The detection of DA was done based on inhibition of the peroxidase-like activity of Fe3O4@C@AgNPs using 3, 3′, 5, 5′-tetramethylbenzidine (TMB) as a substrate. In the presence of DA, however, the peroxidase-like activity started to decrease. The decrease in activity was concentration dependent showing a linear relationship in the range of 0.5–80 µM. In this linear range, the limit of detection (LOD) was computed and found to be as low as 0.12 µM. Therefore, we propose that the peroxidase-like activity of Fe3O4@C@AgNPs could be used for quantitative detection of DA from different samples.

The genetics of cognition in schizophrenia

This conceptual review focuses on recent insights into the nature of the relationship between genetic predisposition and cognitive impairment as risk factors for schizophrenia, and the factors that influence the degree of cognitive impairment in those with the disorder. There is clear evidence that premorbid cognitive impairment is frequently present in those who develop schizophrenia, and, across the range of abilities, poorer premorbid cognition is associated with higher liability to the disorder. Evidence from genetic and population studies strongly supports the hypothesis that premorbid cognitive impairment is a marker for underlying neurodevelopmental risk factors for the disorder, rather than a prodromal manifestation. The premorbid cognitive deficit seems to be largely explained by non-familial factors rather than by familial factors that jointly influence liability to schizophrenia and cognitive ability, and these non-familial risk factors appear act to sensitize individuals to familial risk. There is also evidence that neurodevelopmental risk may be better indexed by the degree to which premorbid cognitive ability deviates from familial expectations than by cognitive ability per se. Premorbid cognitive impairment thus does not itself lie on the causal pathway to schizophrenia, rather it is a marker of a neurodevelopmental abnormality that is substantially non-familial, and which increases risk for schizophrenia. Genetic risk factors, including both common and rare alleles, that influence IQ in the general population also contribute both to liability for schizophrenia and to the degree of cognitive impairment in those with the disorder. There is also evidence for further decline in cognitive function after diagnosis in some individuals as well as an increased risk of dementia. This does not appear to reflect substantial shared heritability with neurodegenerative disorders, but the causes of postonset cognitive decline and its relationship to schizophrenia pathophysiology remain uncertain.