Schizophrenia polygenic risk scores, clinical variables and genetic pathways as predictors of phenotypic traits of bipolar I disorder

J Affect Disord. 2024 Jul 1:356:507-518. doi: 10.1016/j.jad.2024.04.066. Epub 2024 Apr 18.

Abstract

Aim: We investigated the predictive value of polygenic risk scores (PRS) derived from the schizophrenia GWAS (Trubetskoy et al., 2022) (SCZ3) for phenotypic traits of bipolar disorder type-I (BP-I) in 1878 BP-I cases and 2751 controls from Romania and UK.

Methods: We used PRSice-v2.3.3 and PRS-CS for computing SCZ3-PRS for testing the predictive power of SCZ3-PRS alone and in combination with clinical variables for several BP-I subphenotypes and for pathway analysis. Non-linear predictive models were also used.

Results: SCZ3-PRS significantly predicted psychosis, incongruent and congruent psychosis, general age-of-onset (AO) of BP-I, AO-depression, AO-Mania, rapid cycling in univariate regressions. A negative correlation between the number of depressive episodes and psychosis, mainly incongruent and an inverse relationship between increased SCZ3-SNP loading and BP-I-rapid cycling were observed. In random forest models comparing the predictive power of SCZ3-PRS alone and in combination with nine clinical variables, the best predictions were provided by combinations of SCZ3-PRS-CS and clinical variables closely followed by models containing only clinical variables. SCZ3-PRS performed worst. Twenty-two significant pathways underlying psychosis were identified.

Limitations: The combined RO-UK sample had a certain degree of heterogeneity of the BP-I severity: only the RO sample and partially the UK sample included hospitalized BP-I cases. The hospitalization is an indicator of illness severity. Not all UK subjects had complete subphenotype information.

Conclusion: Our study shows that the SCZ3-PRS have a modest clinical value for predicting phenotypic traits of BP-I. For clinical use their best performance is in combination with clinical variables.

Keywords: Bipolar disorder subphenotypes; Individual pathway analysis; Psychosis; Schizophrenia polygenic score.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Bipolar Disorder* / genetics
  • Case-Control Studies
  • Female
  • Genetic Predisposition to Disease* / genetics
  • Genetic Risk Score
  • Genome-Wide Association Study*
  • Humans
  • Male
  • Middle Aged
  • Multifactorial Inheritance* / genetics
  • Phenotype*
  • Polymorphism, Single Nucleotide
  • Psychotic Disorders / genetics
  • Romania
  • Schizophrenia* / genetics
  • United Kingdom