Abstract
The etiologies of bipolar disorder (BD) and schizophrenia include a large number of common risk alleles, many of which are shared across the disorders. BD is clinically heterogeneous and it has been postulated that the pattern of symptoms is in part determined by the particular risk alleles carried, and in particular, that risk alleles also confer liability to schizophrenia influence psychotic symptoms in those with BD. To investigate links between psychotic symptoms in BD and schizophrenia risk alleles we employed a data‐driven approach in a genotyped and deeply phenotyped sample of subjects with BD. We used sparse canonical correlation analysis (sCCA) (Witten, Tibshirani, & Hastie, 2009) to analyze 30 psychotic symptoms, assessed with the OPerational CRITeria checklist, and 82 independent genome‐wide significant single nucleotide polymorphisms (SNPs) identified by the Schizophrenia Working group of the Psychiatric Genomics Consortium for which we had data in our BD sample (3,903 subjects). As a secondary analysis, we applied sCCA to larger groups of SNPs, and also to groups of symptoms defined according to a published factor analyses of schizophrenia. sCCA analysis based on individual psychotic symptoms revealed a significant association (p = .033), with the largest weights attributed to a variant on chromosome 3 (rs11411529), chr3:180594593, build 37) and delusions of influence, bizarre behavior and grandiose delusions. sCCA analysis using the same set of SNPs supported association with the same SNP and the group of symptoms defined “factor 3” (p = .012). A significant association was also observed to the “factor 3” phenotype group when we included a greater number of SNPs that were less stringently associated with schizophrenia; although other SNPs contributed to the significant multivariate association result, the greatest weight remained assigned to rs11411529. Our results suggest that the canonical correlation is a useful tool to explore phenotype–genotype relationships. To the best of our knowledge, this is the first study to apply this approach to complex, polygenic psychiatric traits. The sparse canonical correlation approach offers the potential to include a larger number of fine‐grained systematic descriptors, and to include genetic markers associated with other disorders that are genetically correlated with BD.
Highlights
Bipolar disorder (BD) is a severe, often recurrent, mental illness, associated with disability, suicide, and a reduction in life expectancy of over 10 years (Vos et al, 2015)
FI GURE 2 Correlation matrix between OPCRIT groups of symptoms defined by schizophrenia factor analysis: “factor 1,” “factor 2,” and “factor 3” [Color figure can be viewed at wileyonlinelibrary.com]
If the weights are of opposite sign, they are inversely correlated. Those variables were identified from a single multivariate analysis, and no multiple testing corrections to the p-values are required. sparse CCA (sCCA) for individual psychotic items identified significant association between delusions of influence, bizarre behavior, grandiose delusions, and rs11411529 as in the single nucleotide polymorphism database, reported as indel chr3:180594593, build 37, see Supporting Information Table 2, (The Psychiatric Genomics Consortium, 2014)
Summary
Bipolar disorder (BD) is a severe, often recurrent, mental illness, associated with disability, suicide, and a reduction in life expectancy of over 10 years (Vos et al, 2015). A number of studies have aimed to identify characteristics of the BD phenotype that are most strongly liked to schizophrenia risk, and have generally done so by testing predefined subgroups of BD patients against total burden of schizophrenia risk alleles. While studies of total risk burden are providing insights into the relationships between schizophrenia and BD, a limitation of this approach is that alleles identified from studies of one disorder are considered to act uniformly on a particular symptom, or set of symptoms, in the context of people with the other disorder Given both schizophrenia and BD are highly heterogeneous disorders, if genetic heterogeneity underpins phenotypic heterogeneity, such universal genotype–phenotype relationships are unlikely to apply
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
