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Bipolar disorder risk gene FOXO6 modulates negative symptoms in schizophrenia: a neuroimaging genetics study.

ABSTRACT: BACKGROUND:Despite being diagnostically associated uniquely with schizophrenia, negative symptoms are also observed in bipolar disorder (BD). Genome-wide association studies (GWAS) have uncovered a number of shared risk genes between schizophrenia and BD. The objectives of this study were to examine whether previously identified risk genes for BD are associated with negative symptom severity within a first-episode schizophrenia (FES) cohort and to examine whether such genes influence brain morphology. METHODS:Patients experiencing FES were genotyped for 21 previously identified BD risk genes; a series of univariate analyses of covariance examined the association between negative symptom severity, as measured using the Scale for the Assessment of Negative Symptoms (SANS), and genotype. A subset of participants underwent a structural 1.5 T MRI T1 scan, analyzed for surface area and cortical thickness changes via the CIVET pipeline and LPBA40 atlas. RESULTS:We included 133 patients with FES in our analysis; 61 of them underwent structural MRI. We observed a significant association between negative symptom severity and the BD risk gene FOXO6 (rs4660531). Individuals with the CC genotype presented significantly higher negative symptoms (Cohen d = 0.46, F = 5.854, p = 0.017) and significantly smaller surface area within the right middle orbitofrontal gyrus (Cohen d = 0.69, F = 7.289, p = 0.009) than carriers of allele A. LIMITATIONS:Limitations of this study include its modest sample size and lack of a control sample. CONCLUSION:Lacking the FOXO6 risk allele was associated with an increase in negative symptoms and surface area reduction in the right orbitofrontal gyrus - an area previously associated with negative symptoms - suggesting that presence of the FOXO6 risk allele confers resistance against negative symptoms and associated neuroanatomical changes in individuals with FES.

SUBMITTER: Shenker JJ

PROVIDER: S-EPMC5403662 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

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Bipolar disorder risk gene <i>FOXO6</i> modulates negative symptoms in schizophrenia: a neuroimaging genetics study.

Shenker Joseph J JJ Sengupta Sarojini M SM Joober Ridha R Malla Ashok A Chakravarty M Mallar MM Lepage Martin M

Journal of psychiatry & neuroscience : JPN 20170501 3

<h4>Background</h4>Despite being diagnostically associated uniquely with schizophrenia, negative symptoms are also observed in bipolar disorder (BD). Genome-wide association studies (GWAS) have uncovered a number of shared risk genes between schizophrenia and BD. The objectives of this study were to examine whether previously identified risk genes for BD are associated with negative symptom severity within a first-episode schizophrenia (FES) cohort and to examine whether such genes influence bra ...[more]

PMID: 28234206

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Project description:ImportanceBipolar disorder (BD) is difficult to distinguish from other psychiatric disorders. Neuroimaging studies can identify objective markers of BD risk.ObjectiveTo identify neuroimaging measures in emotion processing and regulation neural circuitries and their associations with symptoms specific to youth at risk for BD.Design, setting, and participantsThis cross-sectional (August 1, 2011, to July 31, 2017) and longitudinal (February 1, 2013, to November 30, 2017) neuroimaging study performed at the University of Pittsburgh Medical Center compared a sample of 31 offspring of parents with BD (OBP) with 28 offspring of comparison parents with non-BD psychopathologies (OCP) and 21 offspring of healthy parents (OHP); OBP, OCP, and OHP were recruited from the Bipolar Offspring Study and the Longitudinal Assessment of Manic Symptoms Study.Main outcomes and measuresGroup differences in activity and functional connectivity during emotional face processing and n-back task performance in amygdala, dorsolateral and ventrolateral prefrontal cortices (PFC), caudal anterior cingulate cortices (cACC), and rostral anterior cingulate cortices (rACC) neuroimaging measures showing between-group differences and symptom severity (anxiety, affective lability, depression, mania). We hypothesized that elevated amygdala activity and/or lower PFC activity and abnormal amygdala to PFC functional connectivity would distinguish OBP from OCP and OHP, and magnitudes of these abnormalities would positively correlate with elevated symptom severity. We explored associations between changes in neuroimaging and symptom measures over follow-up (mean [SD], 2.9 [1.4] years) in a subset of participants (n = 30).ResultsEighty participants were included (mean [SD] age, 14.2 (2.1) years; 35 female). Twelve neuroimaging measures explained 51% of the variance in the results of neuroimaging measures overall. Of the 12, 9 showed significant main associations of the group; however, after post hoc analyses and Bonferroni corrections, only 7 showed statistically significant associations between groups (corrected P < .05 for all). Of the 7, 2 showed significant relationships with symptoms. Offspring of parents with BD had greater right rACC activity when regulating attention to happy faces vs OCP (mean [SD] difference, 0.744 [0.249]; 95% CI, 0.134-1.354; P = .01), which positively correlated with affective lability severity (ρ = 0.304; uncorrected P = .006). Offspring of parents with BD had greater amygdala to left cACC functional connectivity when regulating attention to fearful faces vs OCP (mean [SD] difference, 0.493 [0.169]; 95% CI, 0.079-0.908; P = .01). Increases in this measure positively correlated with increases in affective lability over follow-up (r = 0.541; P = .003).Conclusions and relevanceGreater anterior cingulate cortex activity and functional connectivity during emotion regulation tasks may be specific markers of BD risk. These findings highlight potential neural targets to aid earlier identification of and guide new treatment developments for BD.

Project description:Bipolar disorder is a common, complex genetic disorder, but the mode of transmission remains to be discovered. Many researchers assume that common genomic variants carry some risk for manifesting the disease. The research community has celebrated the first genome-wide significant associations between common single nucleotide polymorphisms (SNPs) and bipolar disorder. Currently, attempts are under way to translate these findings into clinical practice, genetic counseling, and predictive testing. However, some experts remain cautious. After all, common variants explain only a very small percentage of the genetic risk, and functional consequences of the discovered SNPs are inconclusive. Furthermore, the associated SNPs are not disease specific, and the majority of individuals with a "risk" allele are healthy. On the other hand, population-based genome-wide studies in psychiatric disorders have rediscovered rare structural variants and mutations in genes, which were previously known to cause genetic syndromes and monogenic Mendelian disorders. In many Mendelian syndromes, psychiatric symptoms are prevalent. Although these conditions do not fit the classic description of any specific psychiatric disorder, they often show nonspecific psychiatric symptoms that cross diagnostic boundaries, including intellectual disability, behavioral abnormalities, mood disorders, anxiety disorders, attention deficit, impulse control deficit, and psychosis. Although testing for chromosomal disorders and monogenic Mendelian disorders is well established, testing for common variants is still controversial. The standard concept of genetic testing includes at least three broad criteria that need to be fulfilled before new genetic tests should be introduced: analytical validity, clinical validity, and clinical utility. These criteria are currently not fulfilled for common genomic variants in psychiatric disorders. Further work is clearly needed before genetic testing for common variants in psychiatric disorders should be established.

Project description:Bipolar disorder is a mood disorder characterized by impairing episodes of mania and depression. Twin studies have established that bipolar disorder is among the most heritable of medical disorders and efforts to identify specific susceptibility genes have intensified over the past two decades. The search for genes influencing bipolar disorder has been complicated by a paucity of animal models, limited understanding of pathogenesis, and the genetic and phenotypic complexity of the syndrome. Linkage studies have implicated several chromosomal regions as harboring relevant genes, but results have been inconsistent. It is now widely accepted that the genetic liability to bipolar disorder reflects the action of many genes of individually small effect, a scenario for which linkage studies are poorly suited. Thus, association studies, which are more powerful for the detection of modest effect loci, have become the focus of gene-finding research. A large number of candidate genes, including biological candidates derived from hypotheses about the pathogenesis of the disorder and positional candidates derived from linkage and cytogenetic studies, have been evaluated. Several of these genes have been associated with the disorder in independent studies (including BDNF, DAOA, DISC1, GRIK4, SLC6A4, and TPH2), but none has been established. The clinical heterogeneity of bipolar disorder and its phenotypic and genetic overlap with other disorders (especially schizophrenia, schizoaffective disorder, and major depressive disorder) have raised questions about the optimal phenotype definition for genetic studies. Nevertheless, genomewide association analysis, which has successfully identified susceptibility genes for a variety of complex disorders, has begun to implicate specific genes for bipolar disorder (DGKH, CACNA1C, ANK3). The polygenicity of the disorder means that very large samples will be needed to detect the modest effect loci that likely contribute to bipolar disorder. Detailed genetic dissection of the disorder may provide novel targets (both pharmacologic and psychosocial) for intervention.

Project description:Background To compare estimated 10-year and 30-year cardiovascular risk in primary care patients with and without serious mental illness (SMI; bipolar disorder, schizophrenia, or schizoaffective disorder). Methods and Results All patients aged 18 to 75 years with a primary care visit in January 2016 to September 2018 were included and were grouped into those with and without SMI using diagnosis codes. Ten-year cardiovascular risk was estimated using atherosclerotic cardiovascular disease scores for patients aged 40 to 75 years without cardiovascular disease; 30-year cardiovascular risk was estimated using Framingham risk scores for patients aged 18 to 59 years without cardiovascular disease. Demographic, vital sign, medication, diagnosis, and health insurance data were collected from the electronic health record by a clinical decision support system. Descriptive statistics examined unadjusted differences, while general linear models examined differences for continuous variables and logistic regression models for categorical variables. Models were then adjusted for age, sex, race, ethnicity, and insurance type. A total of 11 333 patients with SMI and 579 924 patients without SMI were included. After covariate adjustment, 10-year cardiovascular risk was significantly higher in patients with SMI (mean, 9.44%; 95% CI, 9.29%-9.60%) compared with patients without SMI (mean, 7.99%; 95% CI, 7.97-8.02). Similarly, 30-year cardiovascular risk was significantly higher in those with SMI (25% of patients with SMI in the highest-risk group compared with 11% of patients without SMI; P<0.001). The individual cardiovascular risk factors contributing most to increased risk for those with SMI were elevated body mass index and smoking. Among SMI subtypes, patients with bipolar disorder had the highest 10-year cardiovascular risk, while patients with schizoaffective disorder had the highest 30-year cardiovascular risk. Conclusions The significantly increased cardiovascular risk associated with SMI is evident even in young adults. This suggests the importance of addressing uncontrolled major cardiovascular risk factors in those with SMI at as early an age as possible. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT02451670.

Project description:Autism spectrum disorder (ASD) and schizophrenia (SZ) are heterogenous neurodevelopmental disorders that overlap in symptom presentation. The purpose of this study was to specify overlapping symptom domains and to identify symptoms that can reliably differentiate adults with ASD (n = 53), SZ (n = 39), and typical development (TD; n = 40). All participants regardless of diagnosis were administered gold-standard diagnostic assessments of ASD and SZ characteristics including the Autism Diagnostic Observation Schedule (ADOS-2) and the Positive and Negative Syndrome Scale (PANSS). Sensitivity and specificity of the ADOS were assessed using diagnostic cut-off scores. The degree of symptom overlap on these measures between participant groups was analyzed using Analyses of Variance (ANOVAs), Receiver Operating Characteristic (ROC) Curves, and Analyses of Covariance (ANCOVAs) to control for group differences in IQ and sex distributions. The ADOS reliably discriminated ASD and TD adults, but there was a high rate of "false positives" in SZ patients who did not meet the DSM-5 criteria for ASD. To identify the reasons for low specificity in the SZ sample, we categorized ASD and SZ symptoms into 'positive' (presence of atypical behaviors) and 'negative' (absence of typical behaviors) symptoms. ASD and SZ groups overlapped on negative symptoms largely related to the absence of typical social and communicative behaviors, whereas disorder-specific positive symptoms differentiated ASD and SZ. For example, those with ASD scored higher on restricted and repetitive behaviors and stereotyped language, whereas those with SZ scored higher on psychotic symptoms such as delusions and hallucinations. These results suggest that, when making a differential diagnosis between ASD and SZ, clinicians may benefit from focusing on the presence or absence of positive ASD and SZ symptoms. Standardized measures to classify ASD symptoms into positive and negative symptoms have not yet been developed but represent a potentially viable clinical tool.

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Bipolar disorder risk gene FOXO6 modulates negative symptoms in schizophrenia: a neuroimaging genetics study.

Publications

Bipolar disorder risk gene <i>FOXO6</i> modulates negative symptoms in schizophrenia: a neuroimaging genetics study.

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