Cognitive Endophenotypes Research Articles

An Autistic Endophenotype and Testosterone Are Involved in an Atypical Decline in Selective Attention and Visuospatial Processing in Middle-Aged Women.

Mothers of offspring with autism spectrum disorders (ASD) could present mild forms of their children’s cognitive characteristics, resulting from prenatal brain exposure and sensitivity to testosterone (T). Indeed, their cognition is frequently characterized by hyper-systemizing, outperforming in tests that assess cognitive domains such as selective attention, and fine motor and visuospatial skills. In the general population, all these start to decline around the mid-forties. This study aimed to characterize whether middle-aged women who are biological mothers of individuals with ASD had better performance in the aforementioned cognitive skills than mothers of normative children (in both groups n = 22; mean age = 45), using the standardized Stroop and mirror-drawing tests. We also examined the role of T in their performance in the aforementioned tests. ASD mothers outperformed controls in both tests, giving more correct answers and making fewer mistakes. In addition, they presented higher T levels, which have been associated with better cognitive performance. Cognitive decline in specific skills with aging could be delayed in these middle-aged women, corresponding to a cognitive endophenotype, T playing an important role in this process.

Cognitive deficits in bipolar disorder: from acute episode to remission.

Considerable evidence demonstrates that neuropsychological deficits are prevalent in bipolar disorder during both acute episodes and euthymia. However, it is less clear whether these cognitive disturbances are state- or trait-related. We here present the first longitudinal study employing a within-subject pre- and post-testing examining acutely admitted bipolar patients (BP) in depression or mania and during euthymia, aiming to identify cognitive performance from acute illness to remission. Cognitive performance was measured during acute episodes and repeated after at least 3months of remission. To do so, 55 BP (35 depressed, 20 hypo-/manic) and 55 healthy controls (HC) were tested with a neuropsychological test battery (attention, working memory, verbal memory, executive functioning). The results showed global impairments in acutely ill BP compared to HC: depressed patients showed a characteristic psychomotor slowing, while manic patients had severe deficits in executive functioning. Twenty-nine remitted BP could be measured in the follow-up (dropout rate 48%), whose cognitive functions partially recovered, whereas working memory and verbal memory were still impaired. However, we found that subthreshold depressive symptoms and persisting sleep disturbances in euthymic BP were associated with reduced speed, deficits in attention and verbal memory, while working memory was correlated with psychotic symptoms (lifetime). This result indicates working memory as trait related for a subgroup of BP with psychotic symptoms. In contrast, attention and verbal memory are negatively influenced by state factors like residual symptoms, which should be more considered as possible confounders in the search of cognitive endophenotypes in remitted BP.

Trait self-control is predicted by how reward associations modulate Stroop interference.

Although cognitive control is commonly identified as the basis of self-controlled behavior, correlations found between trait self-control and laboratory measures of cognitive control such as Stroop interference are typically low. Based on the notion that self-control requires the ability to refrain from rewarded behaviors, and inspired by the recent finding that Stroop interference is modulated by reward associations, we propose the idea that the modulation of interference by reward associations (MIRA) is a cognitive marker of trait self-control. Two independent samples of participants completed (1) a modified Stroop task designed to assess MIRA and (2) two common measures of trait self-control: the Brief Self-Control Scale (BSCS) and the Barratt Impulsiveness Scale (BIS-11). MIRA was strongly correlated with the BSCS and moderately correlated with two of the three subscales of the BIS-11. MIRA thus appears to reflect a cognitive endophenotype of individual differences in self-control, and perhaps of related mental disorders.

AB166. Replicative genetic association analysis reveals genetic markers of schizophrenia and Alzheimer’s disease in Russians and Kazakhs and demonstrates overlapping associations pattern between two diseases

Replicative analysis of genetic markers, previously identified in genome-wide association studies (GWAS) for neuropsychiatric diseases, in population of various origins may contribute to better understanding of genetic composition of the diseases. In this study 50 SNPs found in GWAS for schizophrenia (SZ), Alzheimer’s diseases (AD) and cognitive endophenotypes were genotyped in patients and control samples from Russian and Kazakh populations. Eight polymorphic markers (SNPs in regions of genes for APOЕ, APOJ, CSMD1, CCDC60, SNX29, PICALM, NOTCH4 and NRIP1) were associated with AD in Russian population. Associations of 10 genetic markers with SZ in Russian populations (markers in regions of genes for NRGN, KCNB2, NRIP1, CCDC60, LSM1, LOC100129100/LOC100509857, CSMD1, CPVL, POM121L2 and NDE1P1/PRMT6) and 8 genetic markers in Kazakh population (VRK2, KCNB2, CPVL, BRD1, PVRL2, ARHGAP1, CD33 u GPR89P/TRV-AAC1-5) were replicated. Multidimensional reduction methods revealed epistatic interaction of several genetic loci in formation of susceptibility to SZ in populations of various ethnic origins. Overlapping fields of genetic associations for AD and SZ, demonstrating some similarity in inherited background for both diseases, were found. This interaction may be implemented through common unknown levels in pathogenesis of AD and SZ, mediated by cognitive endophenotypes. Bioinformatic analysis of biological functions of associated genes revealed that among primary biological processes enriched by genes under study are the processes of lipid metabolism, cellular interactions, various regulatory and transport processes in neural cells, processes of immune response regulation. Substantial part of investigated genes forms an interacting network, which consisted of distinct clusters corresponding to major biological processes, were genes under study are involved, and to basic molecular functions of their products. In general, data obtained in the project, extend the understanding of genetic component in neuro-psychiatric diseases, as well as the biological processes and functions, implemented in the manifestation of genetic susceptibility to AD and SZ.

Intact interference and inhibitory functions in participants with bipolar disorder and their first-degree relatives

Introduction: Bipolar disorder (BD) is considered a highly heritable disorder. Several cognitive endophenotypes, such as executive functions and verbal memory, have been suggested. A key component of executive functioning is inhibition, a complex construct consisting of various subtypes. Only some of these subtypes have been investigated in BD participants and their relatives. Recent findings suggest that difficulties with more basic functions such as processing speed may account for some of the deficits observed in BD. This possibility has not been explored for inhibitory functions. Method: The current study investigated interference, behavioral and cognitive inhibition, and set-shifting in 36 BD participants, 24 of their unaffected first-degree relatives, and 40 healthy controls. We first used analysis of variance to assess group differences. This was followed by a second analysis in which we controlled for age and processing speed. Results: Group performances after adjustment for age and processing speed were similar in tasks assessing interference and inhibition. However, shifting to a different task set required more time in BD participants than in controls even after adjustment for age and processing speed. BD relatives appeared to show a similar slowing but findings did not reach significance. Conclusions: The findings suggest that responses to interference and inhibitory functions may be preserved in BD participants; however, set-shifting abilities appear to be impaired in BD participants and may be affected in their relatives. Our findings further underline the importance of adjusting for more basic functions such as processing speed when evaluating neuropsychological functions.

Altered inhibition-related frontolimbic connectivity in obsessive-compulsive disorder.

Recent studies have shown that response inhibition is impaired in patients with obsessive-compulsive disorder and their unaffected siblings, suggesting that these deficits may be considered a cognitive endophenotype of obsessive-compulsive disorder. Structural and functional neural correlates of altered response inhibition have been identified in patients and siblings. This study aims to examine the functional integrity of the response inhibition network in patients with obsessive-compulsive disorder and their unaffected siblings. Forty-one unmedicated patients with obsessive-compulsive disorder, 17 of their unaffected siblings and 37 healthy controls performed a stop signal task during functional magnetic resonance imaging. Psycho-physiological interaction analysis was used to examine functional connectivity between the following regions of interest: the bilateral inferior frontal gyri, presupplementary motor area, subthalamic nuclei, inferior parietal lobes, anterior cingulate cortex, and amygdala. We then used dynamic causal modeling to investigate the directionality of the networks involved. Patients, and to a lesser extent also their unaffected siblings, show altered connectivity between the inferior frontal gyrus and the amygdala during response inhibition. The follow-up dynamic causal modeling suggests a bottom-up influence of the amygdala on the inferior frontal gyrus in healthy controls, whereas processing occurs top-down in patients with obsessive-compulsive, and in both directions in siblings. Our findings suggest that amygdala activation in obsessive-compulsive disorder interferes differently with the task-related recruitment of the inhibition network, underscoring the role of limbic disturbances in cognitive dysfunctions in obsessive-compulsive disorder.

First-degree relatives of suicide completers may have impaired decision-making but functional cognitive control

BackgroundThe heritability of suicide is well established. Transmission of risk appears to follow traits more than disorders like depression. In the present project, we aimed at investigating the potential for transmission of cognitive deficits previously observed in suicide attempters, specifically impaired decision-making and cognitive control. MethodsSeventeen healthy first-degree relatives of suicide completers with no personal history of suicidal act were compared to 18 first-degree relatives of individuals with major depressive disorder but no family history of suicidal act, and 19 healthy controls. Decision-making was assessed with the Iowa Gambling Task, and cognitive control with the Stroop Task, the Hayling Sentence Completion Test, and the Trail-Making Test. ResultsBoth suicide and depressed relatives showed lower gambling task net scores than healthy controls. However, there were trends toward lower learning abilities in suicide than depressed relatives (interaction: p = 0.07), with more risky choices at the end of the test. Suicide relatives also showed a higher number of self-corrected errors relative to the total number of errors in the Stroop colour test compared to both control groups, with no difference in interference scores. There was no group-difference for any other cognitive tests. ConclusionOur findings suggest that decision-making impairment may be found in healthy relatives of suicides and represent a cognitive endophenotype of suicidal behaviour. Normal cognitive control (or self-corrected deficits) may protect relatives against suicidal acts. Impairments in value-based and control processes may, therefore, be part of the suicide vulnerability and represent potential targets of preventative interventions.

Age-Related Effects on Response Inhibition in Youth at Familial Risk for Bipolar Disorder

Altered response inhibition, contributing to impulsivity, has been proposed as a cognitive endophenotype of Bipolar Disorder. It remains unclear to what extend bipolar offspring exhibit altered response inhibition compared to offspring of parents with a non bipolar psychopathology and healthy offspring of healthy parents. Behavioral performance during an affective response inhibition task was examined among these groups. Findings suggest that younger bipolar offspring exhibit a deficit in response inhibition to emotional stimuli as evidenced by higher commission errors compared to non bipolar offspring and healthy controls. Findings are consistent with evidence supporting altered early-onset response inhibtion as a cognitive endophenotype of Bipolar Disorder.

How Does Parental Reading Influence Children’s Reading? A Study of Cognitive Mediation

Cognitive processes underlying a behavioural outcome (like reading ability) and the impact of familial risk (e.g., for dyslexia) have been studied in isolation. We present a novel design, linking the two avenues. How do familial influences impact on children’s cognitive skills, which subsequently underlie reading development? Participants from the Familial Influences on Literacy Abilities (FIOLA) Project included 373 children and their parents. We considered three causal routes from parental reading and children’s putative cognitive endophenotypes to children’s reading. Path analyses showed that half of parental effects on children’s reading bypassed and half operated through children’s cognitive underpinnings. Spousal correlation was small but significant. Findings do not support a strong hypothesis of cognitive endophenotypes with full mediation. Furthermore, we discuss the use of parental skills as a proxy for offspring’s liability. Finally, familial reading difficulties are not fully accounted for by known cognitive skills, which has implications for dyslexia diagnosis.

Altered prefrontal cortex activity during working memory task in Bipolar Disorder: A functional Magnetic Resonance Imaging study in euthymic bipolar I and II patients

BackgroundWorking memory (WM) deficits are among the most frequently impaired cognitive domains in patients with Bipolar Disorder (BD), being considered promising cognitive endophenotype of the disorder. However, the related neurobiological correlates still deserve further investigation. The present study was aimed to explore whether dorsolateral prefrontal cortex (DLPFC) activity during WM processing was abnormal in euthymic bipolar patients and may represent a potential trait-related phenotype associated with the disorder. MethodsUsing 3 Tesla functional Magnetic Resonance Imaging (3T fMRI), we studied 28 euthymic bipolar patients (15 BDI and 13 BDII), and 27 healthy controls (HCs), matched for a series of socio-demographic variables, while performing the N-back task for WM assessment. ResultsWe found that euthymic bipolar patients showed increased right middle frontal gyrus engagement compared with HCs (FWE-corrected p=1×10−3), regardless of WM load, and in spite of similar WM behavioral performance between groups. In particular, BDI patients had greater BOLD signal change compared to HCs (post-hoc Tukey HSD, p=1×10−3), while BDII patients expressed an intermediate pattern of activation between BDI patients and HCs. No other significant effects were detected in the corrected whole-brain analysis. LimitationsSample size, cross-sectional assessment and potential influence of some clinical variables. ConclusionsResults provide direct evidence of a primary physiological abnormality in DLPFC function in BDI and II, even in the absence of behavioral differences with HCs. Such exaggerated fMRI response suggests inefficient WM processing in prefrontal circuitry, and further studies are warranted to investigate whether the dysfunction is related to the genetic risk for the disorder.

Interval Timing Deficits Assessed by Time Reproduction Dual Tasks as Cognitive Endophenotypes for Attention-Deficit/Hyperactivity Disorder

The literature has suggested timing processing as a potential endophenotype for attention deficit/hyperactivity disorder (ADHD); however, whether the subjective internal clock speed presented by verbal estimation and limited attention capacity presented by time reproduction could be endophenotypes for ADHD is still unknown. We assessed 223 youths with DSM-IV ADHD (age range: 10-17 years), 105 unaffected siblings, and 84 typically developing (TD) youths using psychiatric interviews, intelligence tests, verbal estimation and time reproduction tasks (single task and simple and difficult dual tasks) at 5-second, 12-second, and 17-second intervals. We found that youths with ADHD tended to overestimate time in verbal estimation more than their unaffected siblings and TD youths, implying that fast subjective internal clock speed might be a characteristic of ADHD, rather than an endophenotype for ADHD. Youths with ADHD and their unaffected siblings were less precise in time reproduction dual tasks than TD youths. The magnitude of estimated errors in time reproduction was greater in youths with ADHD and their unaffected siblings than in TD youths, with an increased time interval at the 17-second interval and with increased task demands on both simple and difficult dual tasks versus the single task. Increased impaired time reproduction in dual tasks with increased intervals and task demands were shown in youths with ADHD and their unaffected siblings, suggesting that time reproduction deficits explained by limited attention capacity might be a useful endophenotype of ADHD.

Neuropsychological dysfunction in adults with early-onset obsessive-compulsive disorder: the search for a cognitive endophenotype.

Evidence suggests that early-onset obsessive-compulsive disorder (OCD) is an etiologically distinct subtype of OCD. The objective of the present work was to search for neurocognitive endophenotypes of early-onset OCD based on assessments of attention, memory, and executive function in patients with the disorder and their unaffected siblings. We compared the performance of 40 adult patients with early-onset OCD, 40 of their unaffected siblings, and 40 unrelated healthy controls on a neuropsychological battery designed for this study. We searched for associations among test performance, demographic variables (age, sex and years of education) and clinical symptoms of early-onset OCD. Patients performed significantly worse than healthy controls on the Tower of Hanoi, and the Stroop and Wisconsin tests, indicating impairments in planning, mental flexibility and inhibitory control. The performance of the unaffected first-degree siblings of patients with early-onset OCD on the Stroop and Wisconsin tests also differed from that of healthy controls. Symptom severity in early-onset OCD was strongly correlated with performance on the Tower of Hanoi. Our findings support the existence of specific executive function deficits in patients with early-onset OCD. Relatives presented an intermediate phenotype between patients and controls, suggesting that executive functions such as mental flexibility and response inhibition may be considered candidate endophenotypes of early-onset OCD.

Impairment of executive functions and memory in unaffected siblings of patients with bipolar disorder

Objective: Neurocognitive impairments in bipolar patients as a possible endophenotype is a growing field of research. Impairments in executive functions and memory have been reported in relatives of patients with bipolar disorder, suggesting that they could be potential endophenotypes for genetic studies. In this study, neuropsychological performance in unaffected siblings of patients diagnosed as bipolar I disorder is compared to that of matched healthy controls. Method: We evaluated 35 unaffected siblings of probands with bipolar I disorder and 35 healthy controls using tests of verbal fluency, attention, executive functions and memory. Rey Auditory Verbal Learning Test (RAVLT), Wechsler Memory Scale-Revised (WMS-R) visual memory test, Stroop Colour-Word Interference test (SCWIT), Trail Making Test-A and B, Wechsler Adult Intelligence Scale-Revised Digit Span test, categoric verbal fluency test (Isaac SET Test) , and clock drawing tests were performed. Results: Unaffected siblings of patients with bipolar disorder performed poorly on the RAVLT, SCWIT, forward Digit Span Test, TMT-A and B, visual recall test. Using stepwise logictic regression TMT-B alone could highly differentiate siblings from controls. Conclusion: We found significant impairment of set shifting task measured with TMT-B in siblings of patients with BD. Our study suggests that set shifting/cognitive flexibility could be a potential cognitive endophenotype for bipolar disorder.

Common genetic variants on 6q24 associated with exceptional episodic memory performance in the elderly.

There are genetic influences on memory ability as we age, but no specific genes have been identified. To use a cognitive endophenotype, exceptional episodic memory (EEM) performance, derived from nondemented offspring from the Long Life Family Study (LLFS) to identify genetic variants that may be responsible for the high cognitive performance of LLFS participants and further replicate these variants using an additional 4006 nondemented individuals from 4 independent elderly cohorts. A total of 467 LLFS participants from 18 families with 2 or more offspring that exhibited exceptional memory performance were used for genome-wide linkage analysis. Adjusted multivariate linear analyses in the 40-megabase region encompassing the linkage peak were conducted using 4 independent replication data sets that included 4006 nondemented elderly individuals. Results of the individual replication cohorts were combined by meta-analysis. Episodic memory scores computed as the mean of the 2 standardized measures of Logical Memory IA and IIA. Heritability estimates indicated a significant genetic component for EEM (h2 = 0.21; SE = 0.09). Genome-wide linkage analysis revealed that EEM was linked to the 6q24 region (maximum logarithm of odds score, 3.64). Association analysis in LLFS families identified single-nucleotide polymorphisms (SNPs) nominally associated with EEM in the 40-megabase window encompassing the linkage peak. Replication in one cohort identified a set of 26 SNPs associated with episodic memory (P ≤ .05). Meta-analysis of the 26 SNPs using the 4 independent replication cohorts found SNPs rs9321334 and rs6902875 to be nominally significantly associated with episodic memory (P = .009 and P = .013, respectively). With meta-analysis restricted to individuals lacking an APOE ε4 allele, SNP rs6902875 became statistically significant (meta-analysis, P = 6.7 × 10-5). Haplotype analysis incorporating the 2 SNPs flanking rs6902875 (rs9321334 and rs4897574) revealed that the A-A-C haplotype was significantly associated with episodic memory performance (P = 2.4 × 10-5). This genomic region harbors monooxygenase dopamine β-hydroxylase-like 1 gene (MOXD1), implicated in the biosynthesis of norepinephrine, which is prominently involved in cognitive functions. The results provide strong evidence for potential candidate genes related to EEM on 6q24. Identifying the genes will help in understanding the biological basis of memory performance and allow interventions for enhancement of cognitive function.

Sex differences in ADHD symptom severity.

Males show higher rates of attention deficit hyperactivity disorder (ADHD) than do females. Potential explanations include genuine etiological differences or artifact. 2,332 twin and sibling youth participated in behavioral and cognitive testing. Partially competing models of symptom severity distribution differences, the mean difference, and variance difference models, were tested within a randomly selected subsample. The Delta method was used to test for mediation of sex differences in ADHD symptom severity by processing speed, inhibition and working memory. The combined mean difference and variance difference models fully explained the sex difference in ADHD symptom severity. Cognitive endophenotypes mediated 14% of the sex difference effect. The sex difference in ADHD symptom severity is valid and may be due to differing genetic and cognitive liabilities between the sexes.

C-23 * Longitudinal Analysis of Verbal Fluency in Chronic Schizophrenia

Objective: It has been argued that semantic verbal fluency may be a promising cognitive endophenotype in schizophrenia and possibly a trait-like cognitive measure of the illness. The present study examined the stability of verbal fluency performance in schizophrenia over-time. It was hypothesized that verbal fluency performance would be stable over 1 year. Method: Data was extracted from a larger study that followed 53 out-patients (16 female; mean age = 39.2 years) diagnosed with schizophrenia or schizoaffective disorder at baseline, 6, and 12 months. At each testing interval, phonemic (i.e., F, A, S) and semantic (i.e., animals) fluency tasks were administered as per Benton (1968) and Butters et al. (1987), respectively. Traditional scoring (i.e., total correct words in one minute/trial) along with phonemic clustering, semantic clustering, phonemic switching, and semantic switching component scores were derived and compared across time points. Results: Linear regression analyses were performed to examine clustering and switching patterns for semantic and phonemic fluency longitudinally. No significant differences (p > 0.05) were found over time. Furthermore, no significant changes in performance were observed over time for both semantic and phonemic mean cluster size or number of switches. Moreover, partial correlation analysis revealed no statistical relationship between phonemic fluency and years of illness. Conclusion(s): The results support the hypothesis in that the component verbal fluency performance across the three time points was stable. Accordingly, the results provide further substantiation to the assertion of verbal fluency as a possible cognitive endophenotype in schizophrenia.

Central coherence in adolescents with bulimia nervosa spectrum eating disorders.

Weak central coherence-a tendency to process details at the expense of the gestalt-has been observed among adults with bulimia nervosa (BN) and is a potential candidate endophenotype for eating disorders (EDs). However, as BN behaviors typically onset during adolescence it is important to assess central coherence in this younger age group to determine whether the findings in adults are likely a result of BN or present earlier in the evolution of the disorder. This study examines whether the detail-oriented and fragmented cognitive inefficiency observed among adults with BN is observable among adolescents with shorter illness duration, relative to healthy controls. The Rey-Osterrieth Complex Figure Test (RCFT) was administered to a total of 47 adolescents with DSM5 BN, 42 with purging disorder (PD), and 25 healthy controls (HC). Performance on this measure was compared across the three groups. Those with BN and PD demonstrated significantly worse accuracy scores compared to controls in the copy and delayed recall condition with a moderate effect size. These findings were exacerbated when symptoms of BN increased. Poorer accuracy scores reflect a fragmented and piecemeal strategy that interferes with visual-spatial integration in BN spectrum disorders. This cognitive inefficiency likely contributes to broad difficulties in executive functioning in this population especially in the context of worsening bulimic symptoms. The findings of this study support the hypothesis that poor global integration may constitute a cognitive endophenotype for BN.

Extension of the generalized disequilibrium test to polytomous phenotypes and two-locus models.

We extend the usual logistic model between a dichotomous phenotype and an allele count in two ways: a polytomous phenotype with K > 2 levels, and modeling of allele counts at two unlinked marker loci. Inference is based on within-family information to guard against potential bias due to population genetic structure. Score tests of the model coefficients taking into account the correlation between relatives in entire pedigrees are derived as an extension of the Generalized Disequilibrium Test (GDT). Simulations confirm that the tests have the expected statistical properties, and that their power exceeds that of the GDT under a favorable scenario. The score tests are illustrated with candidate genetic markers, a major psychosis phenotype and a cognitive endophenotype in large kindreds from Eastern Quebec.

Early impulsivity in youth at familial risk of bipolar disorder

Impulsivity is a core feature of bipolar disorder (BD), and it has even been suggested as a possible cognitive endophenotype of the disorder. Response inhibition is a way to test impulsivity behaviorally. Adults with BD exhibit altered response inhibition in the context of emotionally salient information; however, more studies are needed to determine to what extent youth at risk for BD exhibit altered response inhibition in emotionally salient context. We use the Cambridge Neuropsychological Test Automated Battery (CANTAB), Affective Go/No-Go Task (AGN) to measure response inhibition in the context of emotionally salient information, and hypothesized that in comparison to controls, at-risk BD youth will show altered response inhibition on the AGN task. Results indicate younger BD offspring exhibit more commission errors than controls, and attention deficit hyperactivity disorder (ADHD) diagnoses were not driving the results. Our finding supports response inhibition as a marker of risk for BD or future psychopathology; however, current findings suggest this effect occurs in younger at-risk BD youth.

Genetic influences on cognitive endophenotypes in schizophrenia

BackgroundCognitive deficits are prominent in schizophrenia and represent promising endophenotypes for genetic research. MethodsThe current study investigated the importance of two conceptually distinct genetic aggregates, one based on copy number variations (uncommon deletion burden), and one based on single nucleotide polymorphisms identified in recent risk studies (genetic risk score). The impact of these genetic factors, and their interaction, was examined on cognitive endophenotypes defined by principal component analysis (PCA) in a multi-center sample of 50 patients with schizophrenia and 86 controls. PCA was used to identify three different types of executive function (EF: planning, fluency, and inhibition), and in separate analyses, a measure general cognitive ability (GCA). ResultsCognitive deficits were prominent among individuals with schizophrenia, but no group differences were evident for either genetic factor. Among patients the deletion burden measures predicted cognitive deficits across the three EF components and GCA. Further, an interaction was noted between the two genetic factors for both EF and GCA and the observed patterns of interaction suggested antagonistic epistasis. In general, the set of genetic interactions examined predicted a substantial portion of variance in these cognitive endophenotypes. LimitationsThough adequately powered, our sample size is small for a genetic study. ConclusionsThese results draw attention to genetic interactions and the possibility that genetic influences on cognition differ in patients and controls.