Abstract
Importance Bipolar disorder overlaps with schizophrenia in both its clinical presentation and genetic liability. Alternative approaches to patient stratification beyond the current diagnostic categories are needed to understand the underlying disease processes/mechanisms, and develop new therapeutic interventions.
Objectives To investigate the relationship between common-variant polygenic liability for schizophrenia, as indexed by polygenic risk scores (PRS) and psychotic presentations of bipolar disorder, using clinical descriptions which consider both the occurrence and the level of mood-incongruence of the psychotic symptoms experienced.
Design Case control design: using multinomial logistic regression, to estimate differential associations of the schizophrenia liability across categories of cases and controls.
Settings & Participants 4436 bipolar disorder cases from the UK Bipolar Disorder Research Network, assessed using a unified interview protocol during the period 2000 - 2013. For comparison we included data from the large CLOZUK study of schizophrenia including 4976 treatment resistant schizophrenia cases and UK controls from the Type-1 diabetes genetics consortium (N=2,532) and a subsample of Generation Scotland (N=6,480).
Exposure Standardised Polygenic Risk Scores (PRS) for schizophrenia were generated, using alleles with an association p-value < 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.
Main outcome measure Multinomial logistic regression was used to model the associations of PRS with Bipolar disorder cases stratified by (1) RDC bipolar disorder subtypes (2) Lifetime-ever occurrence of positive and/or disorganised psychotic symptoms (3) Lifetime mood-incongruent psychotic features and (4) ordinal logistic regression modelling the association with mood-incongruence measured on an ordinal scale. Ratings were derived from the Schedule for Clinical Assessment in Neuropsychiatry interview (SCAN), the Operational Criteria checklist (OPCRIT) and the Bipolar Affective Disorder Dimension Scale (BADDS).
Results PRS discriminated CLOZUK cases from controls, with each standard deviation increase in PRS almost doubling the relative risk ratio (RR) (RR=1.94, corrected p-value <0.0001, (95% C.I. 1.86, 2.01)). Across phenotypes, there was a gradient of effect with the strongest PRS association in CLOZUK, then RDC schizoaffective bipolar disorder (RR=1.37, corrected p-value <0.0001, ( 95% C.I. 1.22, 1.54)), RDC bipolar disorder subtype I (RR= 1.30, corrected p-value <0.0001, ( 95% C.I. 1.24, 1.36)) and RDC bipolar disorder subtype II (RR=1.04, p-value 0.258, (95% C.I. 0.97, 1.11)). Within BD cases, there was a gradient of PRS effect, indexed by the nature of psychosis, with the prominence of mood-incongruent psychotic features having the strongest association (RR=1.46, corrected p-value <0.0001, (95% C.I. 1.36, 1.57)), followed by BD with prominence of mood-congruent psychotic features (RR= 1.24, corrected p-value <0.0001, ( 95% C.I. 1.17, 1.33)) and lastly, BD cases with no lifetime occurrence of psychosis (RR=1.09, corrected p-value =0.004, (95% C.I. 1.04, 1.15)).
Conclusion We show for the first time a gradient of schizophrenia risk allele burden, across schizophrenia and bipolar disorder, indexed by the occurrence and level of mood-incongruent positive and disorganised psychotic symptoms.
Question what is the relationship between polygenic liability for schizophrenia and the occurrence and level of mood-incongruent psychotic symptoms in bipolar disorder (BD).
Findings in this case-control study which included 4436 BD and 4976 schizophrenia cases compared with 9012 controls, there was a gradient of schizophrenia polygenic risk scores effects: Schizophrenia > BD with prominent mood-incongruent psychotic features > BD with prominent mood-congruent psychotic features > BD with no psychosis all differential associations were statistically-significant.
Meaning A gradient of schizophrenia liability, across schizophrenia and bipolar disorder, indexed by the occurrence and level of mood-incongruent psychotic symptoms has been shown for the first time