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Identification of sialyltransferase 8B as a generalized susceptibility gene for psychotic and mood disorders on chromosome 15q25-26.

ABSTRACT: We previously identified a significant bipolar spectrum disorder linkage peak on 15q25-26 using 35 extended families with a broad clinical phenotype, including bipolar disorder (types I and II), recurrent unipolar depression and schizoaffective disorder. However, the specific gene(s) contributing to this signal had not been identified. By a fine mapping association study in an Australian case-control cohort (n?=?385), we find that the sialyltransferase 8B (ST8SIA2) gene, coding for an enzyme that glycosylates proteins involved in neuronal plasticity which has previously shown association to both schizophrenia and autism, is associated with increased risk to bipolar spectrum disorder. Nominal single point association was observed with SNPs in ST8SIA2 (rs4586379, P?=?0.0043; rs2168351, P?=?0.0045), and a specific risk haplotype was identified (frequency: bipolar vs controls?=?0.41 vs 0.31; ?(2)?=?6.46, P?=?0.011, OR?=?1.47). Over-representation of the specific risk haplotype was also observed in an Australian schizophrenia case-control cohort (n?=?256) (?(2)?=?8.41, P?=?0.004, OR?=?1.82). Using GWAS data from the NIMH bipolar disorder (n?=?2055) and NIMH schizophrenia (n?=?2550) cohorts, the equivalent haplotype was significantly over-represented in bipolar disorder (?(2)?=?5.91, P?=?0.015, OR?=?1.29), with the same direction of effect in schizophrenia, albeit non-significant (?(2)?=?2.3, P?=?0.129, OR?=?1.09). We demonstrate marked down-regulation of ST8SIA2 gene expression across human brain development and show a significant haplotype×diagnosis effect on ST8SIA2 mRNA levels in adult cortex (ANOVA: F(1,87)?=?6.031, P?=?0.016). These findings suggest that variation the ST8SIA2 gene is associated with increased risk to mental illness, acting to restrict neuronal plasticity and disrupt early neuronal network formation, rendering the developing and adult brain more vulnerable to secondary genetic or environmental insults.

SUBMITTER: McAuley EZ

PROVIDER: S-EPMC3364966 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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Identification of sialyltransferase 8B as a generalized susceptibility gene for psychotic and mood disorders on chromosome 15q25-26.

McAuley Erica Z EZ Scimone Anna A Tiwari Yash Y Agahi Giti G Mowry Bryan J BJ Holliday Elizabeth G EG Donald Jennifer A JA Weickert Cynthia Shannon CS Mitchell Phillip B PB Schofield Peter R PR Fullerton Janice M JM

PloS one 20120531 5

We previously identified a significant bipolar spectrum disorder linkage peak on 15q25-26 using 35 extended families with a broad clinical phenotype, including bipolar disorder (types I and II), recurrent unipolar depression and schizoaffective disorder. However, the specific gene(s) contributing to this signal had not been identified. By a fine mapping association study in an Australian case-control cohort (n = 385), we find that the sialyltransferase 8B (ST8SIA2) gene, coding for an enzyme tha ...[more]

PMID: 22693595

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Project description:BackgroundSex differences in incidence and/or presentation of schizophrenia (SCZ), major depressive disorder (MDD), and bipolar disorder (BIP) are pervasive. Previous evidence for shared genetic risk and sex differences in brain abnormalities across disorders suggest possible shared sex-dependent genetic risk.MethodsWe conducted the largest to date genome-wide genotype-by-sex (G×S) interaction of risk for these disorders using 85,735 cases (33,403 SCZ, 19,924 BIP, and 32,408 MDD) and 109,946 controls from the PGC (Psychiatric Genomics Consortium) and iPSYCH.ResultsAcross disorders, genome-wide significant single nucleotide polymorphism-by-sex interaction was detected for a locus encompassing NKAIN2 (rs117780815, p = 3.2 × 10-8), which interacts with sodium/potassium-transporting ATPase (adenosine triphosphatase) enzymes, implicating neuronal excitability. Three additional loci showed evidence (p < 1 × 10-6) for cross-disorder G×S interaction (rs7302529, p = 1.6 × 10-7; rs73033497, p = 8.8 × 10-7; rs7914279, p = 6.4 × 10-7), implicating various functions. Gene-based analyses identified G×S interaction across disorders (p = 8.97 × 10-7) with transcriptional inhibitor SLTM. Most significant in SCZ was a MOCOS gene locus (rs11665282, p = 1.5 × 10-7), implicating vascular endothelial cells. Secondary analysis of the PGC-SCZ dataset detected an interaction (rs13265509, p = 1.1 × 10-7) in a locus containing IDO2, a kynurenine pathway enzyme with immunoregulatory functions implicated in SCZ, BIP, and MDD. Pathway enrichment analysis detected significant G×S interaction of genes regulating vascular endothelial growth factor receptor signaling in MDD (false discovery rate-corrected p < .05).ConclusionsIn the largest genome-wide G×S analysis of mood and psychotic disorders to date, there was substantial genetic overlap between the sexes. However, significant sex-dependent effects were enriched for genes related to neuronal development and immune and vascular functions across and within SCZ, BIP, and MDD at the variant, gene, and pathway levels.

Project description:Anhedonia is central to multiple psychiatric disorders and causes substantial disability. A dimensional conceptualization posits that anhedonia severity is related to a transdiagnostic continuum of reward deficits in specific neural networks. Previous functional connectivity studies related to anhedonia have focused on case-control comparisons in specific disorders, using region-specific seed-based analyses. Here, the authors explore the entire functional connectome in relation to reward responsivity across a population of adults with heterogeneous psychopathology.In a sample of 225 adults from five diagnostic groups (major depressive disorder, N=32; bipolar disorder, N=50; schizophrenia, N=51; psychosis risk, N=39; and healthy control subjects, N=53), the authors conducted a connectome-wide analysis examining the relationship between a dimensional measure of reward responsivity (the reward sensitivity subscale of the Behavioral Activation Scale) and resting-state functional connectivity using multivariate distance-based matrix regression.The authors identified foci of dysconnectivity associated with reward responsivity in the nucleus accumbens, the default mode network, and the cingulo-opercular network. Follow-up analyses revealed dysconnectivity among specific large-scale functional networks and their connectivity with the nucleus accumbens. Reward deficits were associated with decreased connectivity between the nucleus accumbens and the default mode network and increased connectivity between the nucleus accumbens and the cingulo-opercular network. In addition, impaired reward responsivity was associated with default mode network hyperconnectivity and diminished connectivity between the default mode network and the cingulo-opercular network.These results emphasize the centrality of the nucleus accumbens in the pathophysiology of reward deficits and suggest that dissociable patterns of connectivity among large-scale networks are critical to the neurobiology of reward dysfunction across clinical diagnostic categories.

Project description:BackgroundDepression is the most prevalent mental health problem. The need for effective treatments for depression far outstrips the availability of trained mental health professionals. Smartphones and other widely available technologies are increasingly being leveraged to deliver treatments for depression. Whether there are patient characteristics that affect the potency of smartphone interventions for depression is not well understood.ObjectiveThis study aimed to evaluate whether patient characteristics including clinical diagnosis, depression severity, psychosis status, and current use of antidepressant medications impact the effects of an evidence-based smartphone intervention on depressive symptoms.MethodsData were collected as part of a 2-arm randomized controlled trial comparing a multimodal smartphone intervention called FOCUS with a clinic-based intervention. Here, we report on 82 participants assigned to 12 weeks of FOCUS treatment. We conducted assessments of depressive symptoms using the Beck Depression Inventory-second edition (BDI-II) at baseline, postintervention (3 months), and follow-up (6 months). We tested for differences in the amount of improvement in BDI-II scores from baseline to posttreatment and 6-month follow-up between each of the following patient subgroups using 2 (group) × 2 (time) mixed effects models: diagnosis (ie, schizophrenia spectrum disorder vs bipolar disorder vs major depressive disorder), depression severity (ie, minimal-mild vs moderate-severe depression), psychosis status (ie, presence vs absence of psychotic symptoms), and antidepressant use (ie, taking antidepressants vs not taking antidepressants).ResultsThe majority of participants were male (60%, 49/82), African American (65%, 53/82), and middle-aged (mean age 49 years), with a high school education or lower (62%, 51/82). There were no differences in patient demographics across the variables that were used to stratify the analyses. There was a significant group × time interaction for baseline depression severity (F1,76.8=5.26, P=.02 [posttreatment] and F1,77.4=6.56, P=.01 [6-month follow-up]). Participants with moderate or severe depression had significant improvements (t42=3.20, P=.003 [posttreatment] and t42=4.20, P<.001 [6-month follow-up]), but participants with minimal or mild depression did not (t31=0.20, P=.84 [posttreatment] and t30=0.43, P=.67 [6-month follow-up]). There were no significant group × time interactions for diagnosis, psychosis status, or antidepressant medication use. Participants with minimal or mild depression had negligible nonsignificant improvements (<1 point on the BDI-II). Reduction in depression in all other groups was larger (range 1.7-6.5 points on the BDI-II).ConclusionsOur results suggest that FOCUS can be deployed to treat moderate to severe depressive symptoms among people with schizophrenia spectrum disorders, bipolar disorder, and major depressive disorder, in concert with antidepressant medications or without them, in both people with and without active psychotic symptoms. The study results are consistent with research on transdiagnostic models in psychotherapy and extend our knowledge about the potential of transdiagnostic mobile health.Trial registrationClinicalTrials.gov NCT02421965; http://clinicaltrials.gov/ct2/show/NCT02421965 (Archived by WebCite at http://www.webcitation.org/76pyDlvAS).

Dataset Information

Identification of sialyltransferase 8B as a generalized susceptibility gene for psychotic and mood disorders on chromosome 15q25-26.

Publications

Identification of sialyltransferase 8B as a generalized susceptibility gene for psychotic and mood disorders on chromosome 15q25-26.

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