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Bipolar multiplex families have an increased burden of common risk variants for psychiatric disorders.

ABSTRACT: Multiplex families with a high prevalence of a psychiatric disorder are often examined to identify rare genetic variants with large effect sizes. In the present study, we analysed whether the risk for bipolar disorder (BD) in BD multiplex families is influenced by common genetic variants. Furthermore, we investigated whether this risk is conferred mainly by BD-specific risk variants or by variants also associated with the susceptibility to schizophrenia or major depression. In total, 395 individuals from 33 Andalusian BD multiplex families (166 BD, 78 major depressive disorder, 151 unaffected) as well as 438 subjects from an independent, BD case/control cohort (161 unrelated BD, 277 unrelated controls) were analysed. Polygenic risk scores (PRS) for BD, schizophrenia (SCZ), and major depression were calculated and compared between the cohorts. Both the familial BD cases and unaffected family members had higher PRS for all three psychiatric disorders than the independent controls, with BD and SCZ being significant after correction for multiple testing, suggesting a high baseline risk for several psychiatric disorders in the families. Moreover, familial BD cases showed significantly higher BD PRS than unaffected family members and unrelated BD cases. A plausible hypothesis is that, in multiplex families with a general increase in risk for psychiatric disease, BD development is attributable to a high burden of common variants that confer a specific risk for BD. The present analyses demonstrated that common genetic risk variants for psychiatric disorders are likely to contribute to the high incidence of affective psychiatric disorders in the multiplex families. However, the PRS explained only part of the observed phenotypic variance, and rare variants might have also contributed to disease development.

SUBMITTER: Andlauer TFM

PROVIDER: S-EPMC7985020 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:ObjectivesThis study compared 29 drugs for risk of psychiatric hospitalization in bipolar disorders, addressing the evidence gap on the >50 drugs used by US patients for treatment.MethodsThe Truven Health Analytics MarketScan® database was used to identify 190 894 individuals with bipolar or schizoaffective disorder who filled a prescription for one of 29 drugs of interest: lithium, first- or second-generation antipsychotics, mood-stabilizing anticonvulsants, and antidepressants. Competing risks regression survival analysis was used to compare drugs for risk of psychiatric hospitalization, adjusting for patient age, sex, comorbidities, and pretreatment medications. Other competing risks were ending monotherapy and non-psychiatric hospitalization.ResultsThree drugs were associated with significantly lower risk of psychiatric hospitalization than lithium: valproate (relative risk [RR] = 0.80, P = 3.20 × 10-4 ), aripiprazole (RR = 0.80, P = 3.50 × 10-4 ), and bupropion (RR = 0.80, P = 2.80 × 10-4 ). Eight drugs were associated with significantly higher risk of psychiatric hospitalization: haloperidol (RR = 1.57, P = 9.40 × 10-4 ), clozapine (RR = 1.52, P = .017), fluoxetine (RR = 1.17, P = 3.70 × 10-3 ), sertraline (RR = 1.17, P = 3.20 × 10-3 ), citalopram (RR = 1.14, P = .013), duloxetine (RR = 1.24, P = 5.10 × 10-4 ), venlafaxine (RR = 1.33; P = 1.00 × 10-6 ), and ziprasidone (RR = 1.25; P = 6.20 × 10-3 ).ConclusionsThis largest reported retrospective observational study on bipolar disorders pharmacotherapy to date demonstrates that the majority of patients end monotherapy within 2 months after treatment start. The risk of psychiatric hospitalization varied almost two-fold across individual medications. The data add to the evidence favoring lithium and mood stabilizer use in short-term bipolar disorder management. The findings that the dopaminergic drugs aripiprazole and bupropion had better outcomes than other members of their respective classes and that antidepressant outcomes may vary by baseline mood polarity merit further investigation.

Project description:ImportanceRecurrent copy number variants (rCNVs) have been associated with increased risk of psychiatric disorders in case-control studies, but their population-level impact is unknown.ObjectiveTo provide unbiased population-based estimates of prevalence and risk associated with psychiatric disorders for rCNVs and to compare risks across outcomes, rCNV dosage type (deletions or duplications), and locus features.Design, setting, and participantsThis genetic association study is an analysis of data from the Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH) case-cohort sample of individuals born in Denmark in 1981-2008 and followed up until 2015, including (1) all individuals (n = 92 531) with a hospital discharge diagnosis of attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), bipolar disorder, major depressive disorder (MDD), or schizophrenia spectrum disorder (SSD) and (2) a subcohort (n = 50 625) randomly drawn from the source population. Data were analyzed from January 2021 to August 2023.ExposuresCarrier status of deletions and duplications at 27 autosomal rCNV loci was determined from neonatal blood samples genotyped on single-nucleotide variant microarrays.Main outcomes and measuresPopulation-based rCNV prevalence was estimated with a survey model using finite population correction to account for oversampling of cases. Hazard ratio (HR) estimates and 95% CIs for psychiatric disorders were derived using weighted Cox proportional hazard models. Risks were compared across outcomes, dosage type, and locus features using generalized estimating equation models.ResultsA total of 3547 rCNVs were identified in 64 735 individuals assigned male at birth (53.8%) and 55 512 individuals assigned female at birth (46.2%) whose age at the end of follow-up ranged from 7.0 to 34.7 years (mean, 21.8 years). Most observed increases in rCNV-associated risk for ADHD, ASD, or SSD were moderate, and risk estimates were highly correlated across these disorders. Notable exceptions included high ASD-associated risk observed for Prader-Willi/Angelman syndrome duplications (HR, 20.8; 95% CI, 7.9-55). No rCNV was associated with increased MDD risk. Also, rCNV-associated risk was positively correlated with locus size and gene constraint but not with dosage type. Comparison with published case-control and community-based studies revealed a higher prevalence of deletions and lower associated increase in risk for several rCNVs in iPSYCH2015.Conclusions and relevanceThis study found that several rCNVs were more prevalent and conferred less risk of psychiatric disorders than estimated previously. Most case-control studies overestimate rCNV-associated risk of psychiatric disorders, likely because of selection bias. In an era where genetics is increasingly being clinically applied, these results highlight the importance of population-based risk estimates for genetics-based predictions.

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Bipolar multiplex families have an increased burden of common risk variants for psychiatric disorders.

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