Date Published: April 19, 2018
Publisher: John Wiley and Sons Inc.
Author(s): Ganna Leonenko, Arianna Di Florio, Judith Allardyce, Liz Forty, Sarah Knott, Lisa Jones, Katherine Gordon‐Smith, Michael J. Owen, Ian Jones, James Walters, Nick Craddock, Michael C. O’Donovan, Valentina Escott‐Price.
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.
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). Pervasive high mood and increased energy are core features of the disorder, characteristically alternating with spells of depression and normal mood states (Vázquez, Holtzman, Lolich, Ketter, & Baldessarini, 2015). BD is clinically heterogeneous; psychotic symptoms are present in some individuals but not others, and when these occur, they can be indistinguishable from those present in people with schizophrenia (Craddock, O’donovan, & Owen, 2005; Grande, Berk, Birmaher, & Vieta, 2016).
First, we performed sCCA for 82 genome‐wide significant (GWS) SNPs and 30 individual OPCRIT symptoms. The results are summarized in Table 2. Phenotypes and genotypes with nonzero weights chosen by sCCA are shown in columns “phenotypes” and “SNPs,” respectively. Weights can be interpreted as unstandardized regression coefficients and can be negative or positive (Supporting Information Table 2). If weights for phenotype variables and SNP variables are of the same sign that indicates that both variables are positively correlated. If the weights are of opposite sign, then they are inversely correlated. Those variables were identified from a single multivariate analysis, and therefore no multiple testing corrections to the p‐values are required. 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 (dbSNP) (http://www.ncbi.nlm.nih.gov/projects/SNP), also reported as indel chr3:180594593, build 37, see Supporting Information Table 2, (The Psychiatric Genomics Consortium, 2014). Delusions of influence, grandiose delusions had the largest contribution to the sCCA loadings (Supporting Information Table 3).
BD and schizophrenia are distinct categorical entities according to current diagnostic systems. Nevertheless, the two disorders share many clinical features—for example, up to 50% of patients with BD present with symptoms that are common in schizophrenia such as persecutory delusions, auditory hallucinations, experiences of influence, and catatonic symptoms (Pope & Lipinski, 1978) and it is now clear their genetic etiologies also substantially overlap. The relationships, if any, between the genetic and clinical overlaps are unclear, although recent studies suggest schizophrenia risk is particularly elevated in people with BD and mood incongruent psychotic features (Allardyce et al., 2017; Goes et al., 2012).