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VEGFA GENE variation influences hallucinations and frontotemporal morphology in psychotic disorders: a B-SNIP study.

ABSTRACT: Vascular endothelial growth factor A (VEGFA) dysfunction may contribute to a number of pathological processes that characterize psychotic disorders. However, the influence of VEGFA gene variants on clinical and neuroimaging phenotypes in psychotic disorders has yet to be shown. In the present study, we examined whether different VEGFA gene variants influence psychosis risk, symptom severity, cognition, and brain volume. The study group included 480 probands (Bipolar I disorder with psychosis, n?=?205; Schizoaffective disorder, n?=?112; Schizophrenia, n?=?163) and 126 healthy controls that were recruited across six sites in the B-SNIP consortium. VEGFA variants identified for analysis (rs699947, rs833070, and rs2146323) were quantified via SNP chip array. We assessed symptoms and cognition using standardized clinical and neuropsychological batteries. The dorsolateral prefrontal cortex (DLPFC), medial temporal lobe, and hippocampal volumes were quantified using FreeSurfer. In our sample, VEGFA rs2146323 A- carriers showed reduced odds of being a proband (p?=?0.037, OR?=?0.65, 95% CI?=?0.43-0.98) compared to noncarriers, but not for rs699947 or rs833070. In probands, rs2146323 A- carriers demonstrated fewer hallucinations (p?=?0.035, Cohen's d?=?0.194), as well as significantly greater DLPFC (p?

SUBMITTER: Lizano P

PROVIDER: S-EPMC6181939 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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VEGFA GENE variation influences hallucinations and frontotemporal morphology in psychotic disorders: a B-SNIP study.

Lizano Paulo P Lutz Olivia O Ling George G Padmanabhan Jaya J Tandon Neeraj N Sweeney John J Tamminga Carol C Pearlson Godfrey G Ruaño Gualberto G Kocherla Mohan M Windemuth Andreas A Clementz Brett B Gershon Elliot E Keshavan Matcheri M

Translational psychiatry 20181011 1

Vascular endothelial growth factor A (VEGFA) dysfunction may contribute to a number of pathological processes that characterize psychotic disorders. However, the influence of VEGFA gene variants on clinical and neuroimaging phenotypes in psychotic disorders has yet to be shown. In the present study, we examined whether different VEGFA gene variants influence psychosis risk, symptom severity, cognition, and brain volume. The study group included 480 probands (Bipolar I disorder with psychosis, n ...[more]

PMID: 30310054

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Project description:Eye movement deviations, particularly deficits of initial sensorimotor processing and sustained pursuit maintenance, and antisaccade inhibition errors, are established intermediate phenotypes for psychotic disorders. We here studied eye movement measures of 849 participants from the Bipolar-Schizophrenia Network on Intermediate Phenotypes (B-SNIP) study (schizophrenia N=230, schizoaffective disorder N=155, psychotic bipolar disorder N=206 and healthy controls N=258) as quantitative phenotypes in relation to genetic data, while controlling for genetically derived ancestry measures, age and sex. A mixed-modeling genome-wide association studies approach was used including ~4.4 million genotypes (PsychChip and 1000 Genomes imputation). Across participants, sensorimotor processing at pursuit initiation was significantly associated with a single nucleotide polymorphism in IPO8 (12p11.21, P=8 × 10-11), whereas suggestive associations with sustained pursuit maintenance were identified with SNPs in SH3GL2 (9p22.2, P=3 × 10-8). In participants of predominantly African ancestry, sensorimotor processing was also significantly associated with SNPs in PCDH12 (5q31.3, P=1.6 × 10-10), and suggestive associations were observed with NRSN1 (6p22.3, P=5.4 × 10-8) and LMO7 (13q22.2, P=7.3x10-8), whereas antisaccade error rate was significantly associated with a non-coding region at chromosome 7 (P=6.5 × 10-9). Exploratory pathway analyses revealed associations with nervous system development and function for 40 top genes with sensorimotor processing and pursuit maintenance (P=4.9 × 10-2-9.8 × 10-4). Our findings suggest novel patterns of genetic variation relevant for brain systems subserving eye movement control known to be impaired in psychotic disorders. They include genes involved in nuclear trafficking and gene silencing (IPO8), fast axonal guidance and synaptic specificity (PCDH12), transduction of nerve signals (NRSN1), retinal degeneration (LMO7), synaptic glutamate release (SH3GL2), and broader nervous system development and function.

Project description:BackgroundAuditory hallucinations are prevalent across the major psychotic disorders, but their underlying mechanism is poorly understood. Limited prior work supports a hypothesis of altered auditory/language brain systems. To more definitively assess this, we examined whether alterations in resting state connectivity of auditory and language cortices are associated with hallucination severity in a large sample of individuals in the schizo-bipolar spectrum.MethodsWhole brain resting state connectivity of auditory and language cortex (primary auditory cortex, unimodal auditory association cortex, Wernicke's area [speech and heteromodal association cortex] and Broca's area [speech production motor]) was evaluated for 243 subjects with schizophrenia, schizoaffective, or bipolar disorder with psychosis and 186 healthy controls from the Bipolar Schizophrenia Network on Intermediate Phenotypes (B-SNIP) study. Regression analyses were conducted to evaluate whether resting state connectivity of auditory and language cortex was a significant predictor of current overall hallucination severity (information about specific modality of hallucinations experienced was not available).ResultsIncreased connectivity between lower and higher order regions of left temporal-parietal auditory/language processing cortex was associated with worse hallucination severity for all psychosis patients. Additionally, within bipolar subjects, increased interhemispheric connectivity between higher order temporal-parietal auditory/language regions was related to greater hallucination severity. When patients were categorized by B-SNIP biomarker-based Biotype groups, interhemispheric connectivity between left auditory association cortex and right core auditory cortex was related to greater hallucination severity for Biotype 1 patients. Exploratory analyses resulted in different patterns of connectivity of auditory/language cortex in patients and controls, unrelated to current hallucination severity.ConclusionsAlthough the findings cannot be precisely attributed to auditory hallucination severity or possible differences in such experiences between groups, increased connectivity among the left hemisphere auditory and receptive language cortex may represent a significant factor contributing to hallucination severity across psychotic disorders, and additional subgroup specific connectivity alterations may also be present.

Project description:BACKGROUND:Difficulty recognizing facial emotions is an important social-cognitive deficit associated with psychotic disorders. It also may reflect a familial risk for psychosis in schizophrenia-spectrum disorders and bipolar disorder. OBJECTIVE:The objectives of this study from the Bipolar-Schizophrenia Network on Intermediate Phenotypes (B-SNIP) consortium were to: 1) compare emotion recognition deficits in schizophrenia, schizoaffective disorder and bipolar disorder with psychosis, 2) determine the familiality of emotion recognition deficits across these disorders, and 3) evaluate emotion recognition deficits in nonpsychotic relatives with and without elevated Cluster A and Cluster B personality disorder traits. METHOD:Participants included probands with schizophrenia (n=297), schizoaffective disorder (depressed type, n=61; bipolar type, n=69), bipolar disorder with psychosis (n=248), their first-degree relatives (n=332, n=69, n=154, and n=286, respectively) and healthy controls (n=380). All participants completed the Penn Emotion Recognition Test, a standardized measure of facial emotion recognition assessing four basic emotions (happiness, sadness, anger and fear) and neutral expressions (no emotion). RESULTS:Compared to controls, emotion recognition deficits among probands increased progressively from bipolar disorder to schizoaffective disorder to schizophrenia. Proband and relative groups showed similar deficits perceiving angry and neutral faces, whereas deficits on fearful, happy and sad faces were primarily isolated to schizophrenia probands. Even non-psychotic relatives without elevated Cluster A or Cluster B personality disorder traits showed deficits on neutral and angry faces. Emotion recognition ability was moderately familial only in schizophrenia families. CONCLUSIONS:Emotion recognition deficits are prominent but somewhat different across psychotic disorders. These deficits are reflected to a lesser extent in relatives, particularly on angry and neutral faces. Deficits were evident in non-psychotic relatives even without elevated personality disorder traits. Deficits in facial emotion recognition may reflect an important social-cognitive deficit in patients with psychotic disorders.

Dataset Information

VEGFA GENE variation influences hallucinations and frontotemporal morphology in psychotic disorders: a B-SNIP study.

Publications

VEGFA GENE variation influences hallucinations and frontotemporal morphology in psychotic disorders: a B-SNIP study.

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