Psychosis and the level of mood incongruence in Bipolar Disorder are related to genetic liability for Schizophrenia

Allardyce, J.; Leonenko, G.; Hamshere, M.; Pardinas, A.; Forty, L.; Knott, S.; Gordon-Smith, K.; Porteous, D.; Hayward, C.; Di Florio, A.; Jones, L.; McIntosh, A.; Owen, M. J.; Holmans, P.; Walters, J.; Craddock, N.; Jones, I.; O'Donovan, M. C.; Escott-Price, V.

doi:10.1101/160119

bioRxiv · 10.1101/160119

Psychosis and the level of mood incongruence in Bipolar Disorder are related to genetic liability for Schizophrenia

Allardyce, J.·Leonenko, G.·Hamshere, M.·Pardinas, A.·Forty, L.·Knott, S.·Gordon-Smith, K.·Porteous, D.·Hayward, C.·Di Florio, A.·Jones, L.·McIntosh, A.·Owen, M. J.·Holmans, P.·Walters, J.·Craddock, N.·Jones, I.·O'Donovan, M. C.·Escott-Price, V.

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Abstract

ImportanceBipolar disorder (BD) overlaps schizophrenia in its clinical presentation and genetic liability. Alternative approaches to patient stratification beyond current diagnostic categories are needed to understand the underlying disease processes/mechanisms.\n\nObjectivesTo investigate the relationship between common-variant liability for schizophrenia, indexed by polygenic risk scores (PRS) and psychotic presentations of BD, using clinical descriptions which consider both occurrence and level of mood-incongruent psychotic features.\n\nDesignCase-control design: using multinomial logistic regression, to estimate differential associations of PRS across categories of cases and controls.\n\nSettings & Participants4399 BDcases, mean [sd] age-at-interview 46[12] years, of which 2966 were woman (67%) from the BD Research Network (BDRN) were included in the final analyses, with data for 4976 schizophrenia cases and 9012 controls from the Type-1 diabetes genetics consortium and Generation Scotland included for comparison.\n\nExposureStandardised PRS, calculated using alleles with an association p-value threshold < 0.05 in the second Psychiatric Genomics Consortium genome-wide association study of schizophrenia, adjusted for the first 10 population principal components and genotyping-platform.\n\nMain outcome measureMultinomial logit models estimated PRS associations with BD stratified by (1) Research Diagnostic Criteria (RDC) BD subtypes (2) Lifetime occurrence of psychosis.(3) Lifetime mood-incongruent psychotic features and (4) ordinal logistic regression examined PRS associations across levels of mood-incongruence. Ratings were derived from the Schedule for Clinical Assessment in Neuropsychiatry interview (SCAN) and the Bipolar Affective Disorder Dimension Scale (BADDS).\n\nResultsAcross clinical phenotypes, there was an exposure-response gradient with the strongest PRS association for schizophrenia (RR=1.94, (95% C.1.1.86, 2.01)), then schizoaffective BD (RR=1.37, (95% C.I. 1.22, 1.54)), BD I (RR= 1.30, (95% C.I. 1.24, 1.36)) and BD II (RR=1.04, (95% C.1. 0.97, 1.11)). Within BD cases, there was an effect gradient, indexed by the nature of psychosis, with prominent mood-incongruent psychotic features having the strongest association (RR=1.46, (95% C.1.1.36, 1.57)), followed by mood-congruent psychosis (RR= 1.24, (95% C.1. 1.17, 1.33)) and lastly, BD cases with no history of psychosis (RR= 1.09, (95% C.1. 1.04, 1.15)).\n\nConclusionWe show for the first time a polygenic-risk gradient, across schizophrenia and bipolar disorder, indexed by the occurrence and level of mood-incongruent psychotic symptoms.

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Allardyce, J., Leonenko, G., Hamshere, M., Pardinas, A., Forty, L., Knott, S., Gordon-Smith, K., Porteous, D., Hayward, C., Di Florio, A., Jones, L., McIntosh, A., Owen, M. J., Holmans, P., Walters, J., Craddock, N., Jones, I., O'Donovan, M. C., Escott-Price, V.. 2017-07-06. Psychosis and the level of mood incongruence in Bipolar Disorder are related to genetic liability for Schizophrenia. https://doi.org/10.1101/160119

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