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Genomewide association analyses of electrophysiological endophenotypes for schizophrenia and psychotic bipolar disorders: a preliminary report.

ABSTRACT: Several event-related potentials (ERP), including P3, sensory gating (P50), and gamma oscillation, are robustly impaired in patients with schizophrenia (SCZ) and bipolar disorder (BIP). Although these ERPs are known to be heritable, little is known about the specific genetic loci involved and the degree to which they overlap with loci influencing mood and psychotic disorders. In the present study, we conducted GWAS to a) identify common variants associated with ERP endophenotypes, and b) construct polygenic risk scores (PRS) to examine overlap between genetic components of ERPs and mood and psychotic disorders. The sample consisted of 271 patients with SCZ or psychotic BIP diagnosis and 128 controls for whom ERP and genomewide data were available. GWAS were conducted using the full sample. PRS, derived from the Psychiatric Genomics Consortium (PGC) analyses of SCZ, BIP, and major depressive disorder were applied to each ERP phenotype. We identified a region on chromosome 14 that was significantly associated with sensory gating (peak SNP rs10132223, P?=?1.27?×?10(-9) ). This locus has not been previously associated with psychotic illness in PGC-GWAS. In the PRS analyses, patients with a higher load of SCZ risk alleles had reduced gamma response whereas patients with a higher load of BIP risk alleles had smaller P3 amplitude. We observed a genomewide significant locus on chromosome 14 for P50. This locus may influence P50 but not psychotic illness. Among patients with psychotic illness, PRS results indicated genetic overlap between SCZ loci and gamma oscillation and between BIP loci and P3 amplitude.

SUBMITTER: Hall MH

PROVIDER: S-EPMC4458348 | biostudies-literature | 2015 Apr

REPOSITORIES: biostudies-literature

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Genomewide association analyses of electrophysiological endophenotypes for schizophrenia and psychotic bipolar disorders: a preliminary report.

Hall Mei-Hua MH Chen Chia-Yen CY Cohen Bruce M BM Spencer Kevin M KM Levy Deborah L DL Öngür Dost D Smoller Jordan W JW

American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 20150304 3

Several event-related potentials (ERP), including P3, sensory gating (P50), and gamma oscillation, are robustly impaired in patients with schizophrenia (SCZ) and bipolar disorder (BIP). Although these ERPs are known to be heritable, little is known about the specific genetic loci involved and the degree to which they overlap with loci influencing mood and psychotic disorders. In the present study, we conducted GWAS to a) identify common variants associated with ERP endophenotypes, and b) constru ...[more]

PMID: 25740047

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Project description:BACKGROUND:Quantitative endophenotypes are needed to better understand the pathogenesis of schizophrenia. The psychobiological model of temperament and character suggests that personality traits are heritable and regulated by brain systems influencing schizophrenia susceptibility. Thus, measures of temperament and character may serve as schizophrenia-related endophenotypes in individuals with schizophrenia and their non-psychotic siblings. METHODS:Individuals with schizophrenia (n=35), their non-psychotic siblings (n=34), controls (n=63), and their siblings (n=56) participated in a study of the clinical, neurocognitive and neuromorphological characteristics of schizophrenia. A mixed-model approach assessed group differences on the Temperament and Character Inventory (TCI). Neurocognitive deficits and psychopathology were correlated with the TCI. Configurations of TCI domains were examined using a generalized linear model. RESULTS:Individuals with schizophrenia and their non-psychotic siblings had higher harm avoidance than controls and their siblings. Individuals with schizophrenia had lower self-directedness and cooperativeness, and higher self-transcendence than their non-psychotic siblings, controls, and the siblings of controls. Neurocognition was not related to temperament and character in individuals with schizophrenia or either control group. In non-psychotic siblings, self-directedness and cooperativeness were correlated with working memory and crystallized IQ. CONCLUSION:Evidence supports harm avoidance as a schizophrenia-related endophenotype. An increased risk of schizophrenia may be associated with asociality (configured as high harm avoidance and low reward dependence), schizotypy (configured as low self-directedness, low cooperativeness, and high self-transcendence), and neurocognitive deficits (poor executive functioning, working/episodic memory, attention, and low IQ). The non-psychotic siblings demonstrated features of a mature character profile including strong crystallized IQ, which may confer protection against psychopathology.

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.

Project description:OBJECTIVE:Family and twin studies indicate substantial overlap of genetic influences on psychotic and mood disorders. Linkage and candidate gene studies have also suggested overlap across schizophrenia, bipolar disorder, and major depressive disorder. The purpose of this study was to apply genomewide association study (GWAS) analysis to address the specificity of genetic effects on these disorders. METHOD:The authors combined GWAS data from three large effectiveness studies of schizophrenia (CATIE, genotyped: N=741), bipolar disorder (STEP-BD, geno-typed: N=1,575), and major depressive disorder (STAR*D, genotyped: N=1,938) as well as from psychiatrically screened control subjects (NIMH-Genetics Repository: N=1,204). A two-stage analytic procedure involving an omnibus test of allele frequency differences among case and control groups was applied, followed by a model selection step to identify the best-fitting model of allelic effects across disorders. RESULTS:The strongest result was seen for a single nucleotide polymorphism near the adrenomedullin (ADM) gene (rs6484218), with the best-fitting model indicating that the effect was specific to bipolar II disorder. Findings also revealed evidence suggesting that several genes may have effects that transcend clinical diagnostic boundaries, including variants in NPAS3 that showed pleiotropic effects across schizophrenia, bipolar disorder, and major depressive disorder. CONCLUSIONS:This study provides the first genomewide significant evidence implicating variants near the ADM gene on chromosome 11p15 in psychopathology, with effects that appear to be specific to bipolar II disorder. Although genomewide significant evidence of cross-disorder effects was not detected, the results provide evidence that there are both pleiotropic and disorder-specific effects on major mental illness and illustrate an approach to dissecting the genetic basis of mood and psychotic disorders that can inform future large-scale cross-disorder GWAS analyses.

Dataset Information

Genomewide association analyses of electrophysiological endophenotypes for schizophrenia and psychotic bipolar disorders: a preliminary report.

Publications

Genomewide association analyses of electrophysiological endophenotypes for schizophrenia and psychotic bipolar disorders: a preliminary report.

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