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Variants in the 15q25 gene cluster are associated with risk for schizophrenia and bipolar disorder.

ABSTRACT: BACKGROUND:Rates of tobacco smoking are significantly higher in patients with schizophrenia compared with the general population. The underlying mechanism for this comorbidity is unclear. One hypothesis is that there are common genetic factors that predispose to both nicotine dependence (ND) and schizophrenia. To investigate this hypothesis, we examined the association of the 15q25 gene cluster, the most significant candidate region to date implicated in ND and smoking behavior, with schizophrenia and bipolar disorder. METHODS:Five variants in the 15q25 gene cluster (rs951266, rs16969968, rs1051730, rs8040868, and rs17477223) were selected to test for association with schizophrenia diagnosis, bipolar disorder diagnosis, and the presence of negative symptoms of schizophrenia. Effects of the variants on 15q25 gene expression were analyzed using publically available postmortem brain expression data. RESULTS:A meta-analysis revealed four markers associated with risk for schizophrenia and bipolar disorder (rs951266, rs16969968, rs8040868, and rs17477223), and with the presence of negative symptoms of schizophrenia (rs951266, rs1051730, rs8040868, and rs17477223). The associations were in the same direction as that found for ND. Gene expression analysis indicated an association between genotypes of the rs1051730 variant and CHRNA5 expression in brain and peripheral blood mononuclear cells, and with the rs16969968 and rs17477223 variants in brain. CONCLUSION:Variants in the 15q25 gene cluster are associated with risk for schizophrenia/bipolar illness, negative symptoms of schizophrenia, and influence CHRNA5 expression in the brain and peripheral blood mononuclear cells. These results are consistent with the notion that there are genetic mechanisms common to schizophrenia, ND, and bipolar disorder.

SUBMITTER: Jackson KJ

PROVIDER: S-EPMC3644701 | biostudies-literature | 2013 Feb

REPOSITORIES: biostudies-literature

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Variants in the 15q25 gene cluster are associated with risk for schizophrenia and bipolar disorder.

Jackson Kia J KJ Fanous Ayman H AH Chen Jingchun J Kendler Kenneth S KS Chen Xiangning X

Psychiatric genetics 20130201 1

<h4>Background</h4>Rates of tobacco smoking are significantly higher in patients with schizophrenia compared with the general population. The underlying mechanism for this comorbidity is unclear. One hypothesis is that there are common genetic factors that predispose to both nicotine dependence (ND) and schizophrenia. To investigate this hypothesis, we examined the association of the 15q25 gene cluster, the most significant candidate region to date implicated in ND and smoking behavior, with sch ...[more]

PMID: 23196875

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Project description:BACKGROUND:A challenge of understanding the mechanisms underlying cognition including neurodevelopmental and neuropsychiatric disorders is mainly given by the potential severity of cognitive disorders for the quality of life and their prevalence. However, the field has been focused predominantly on protein coding variation until recently. Given the importance of tightly controlled gene expression for normal brain function, the goal of the study was to assess the functional variation including non-coding variation in human genome that is likely to play an important role in cognitive functions. To this end, we organized and utilized available genome-wide datasets from genomic, transcriptomic and association studies into a comprehensive data corpus. We focused on genomic regions that are enriched in regulatory activity-overlapping transcriptional factor binding regions and repurpose our data collection especially for identification of the regulatory SNPs (rSNPs) that showed associations both with allele-specific binding and allele-specific expression. We matched these rSNPs to the nearby and distant targeted genes and then selected the variants that could implicate the etiology of cognitive disorders according to Genome-Wide Association Studies (GWAS). Next, we use DeSeq 2.0 package to test the differences in the expression of the certain targeted genes between the controls and the patients that were diagnosed bipolar affective disorder and schizophrenia. Finally, we assess the potential biological role for identified drivers of cognition using DAVID and GeneMANIA. RESULTS:As a result, we selected fourteen regulatory SNPs locating within the loci, implicated from GWAS for cognitive disorders with six of the variants unreported previously. Grouping of the targeted genes according to biological functions revealed the involvement of processes such as 'posttranscriptional regulation of gene expression', 'neuron differentiation', 'neuron projection development', 'regulation of cell cycle process' and 'protein catabolic processes'. We identified four rSNP-targeted genes that showed differential expression between patient and control groups depending on brain region: NRAS-in schizophrenia cohort, CDC25B, DDX21 and NUCKS1-in bipolar disorder cohort. CONCLUSIONS:Overall, our findings are likely to provide the keys for unraveling the mechanisms that underlie cognitive functions including major depressive disorder, bipolar disorder and schizophrenia etiopathogenesis.

Project description:ImportanceAdults with schizophrenia, schizoaffective disorder, or bipolar disorder, collectively termed serious mental illness (SMI), have shortened life spans compared with people without SMI. The leading cause of death is cardiovascular (CV) disease.ObjectiveTo assess whether a clinical decision support (CDS) system aimed at primary care clinicians improves CV health for adult primary care patients with SMI.Design, setting, and participantsIn this cluster randomized clinical trial conducted from March 2, 2016, to September 19, 2018, restricted randomization assigned 76 primary care clinics in 3 Midwestern health care systems to receive or not receive a CDS system aimed at improving CV health among patients with SMI. Eligible clinics had at least 20 patients with SMI; clinicians and their adult patients with SMI with at least 1 modifiable CV risk factor not at the goal set by the American College of Cardiology/American Heart Association guidelines were included. Statistical analysis was conducted on an intention-to-treat basis from January 10, 2019, to December 29, 2021.InterventionThe CDS system assessed modifiable CV risk factors and provided personalized treatment recommendations to clinicians and patients.Main outcomes and measuresPatient-level change in total modifiable CV risk over 12 months, summed from individual modifiable risk factors (smoking, body mass index, low-density lipoprotein cholesterol level, systolic blood pressure, and hemoglobin A1c level).ResultsA total of 80 clinics were randomized; 4 clinics were excluded for having fewer than 20 eligible patients, leaving 42 intervention clinics and 34 control clinics. A total of 8937 patients with SMI (4922 women [55.1%]; mean [SD] age, 48.4 [13.5] years) were enrolled. There was a 4% lower rate of increase in total modifiable CV risk among intervention patients relative to control patients (relative rate ratio [RR], 0.96; 95% CI, 0.94-0.98). The intervention favored patients who were 18 to 29 years of age (RR, 0.89; 95% CI, 0.81-0.98) or 50 to 59 years of age (RR, 0.93; 95% CI, 0.90-0.96), Black (RR, 0.93; 95% CI, 0.88-0.98), or White (RR, 0.96; 95% CI, 0.94-0.98). Men (RR, 0.96; 95% CI, 0.94-0.99) and women (RR, 0.95; 95% CI, 0.92-0.97), as well as patients with any SMI subtype (bipolar disorder: RR, 0.96; 95% CI, 0.94-0.99; schizoaffective disorder: RR, 0.94; 95% CI, 0.90-0.98; schizophrenia: RR, 0.92; 95% CI, 0.85-0.99) also benefited from the intervention. Despite treatment effects favoring the intervention, there were no significant differences in individual modifiable risk factors.Conclusions and relevanceThis CDS intervention resulted in a rate of change in total modifiable CV risk that was 4% lower among intervention patients compared with control patients. Results were driven by the cumulative effects of incremental and mostly nonsignificant changes in individual modifiable risk factors. These findings emphasize the value of using CDS to prompt early primary care intervention for adults with SMI.Trial registrationClinicalTrials.gov Identifier: NCT02451670.

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Variants in the 15q25 gene cluster are associated with risk for schizophrenia and bipolar disorder.

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Variants in the 15q25 gene cluster are associated with risk for schizophrenia and bipolar disorder.

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