Genetic Evidence for the Psychosis Continuum: A Polygenic Score Analysis

TY - JOUR

T1 - Genetic Evidence for the Psychosis Continuum: A Polygenic Score Analysis

AU - Haussler, Senta

AU - Prata, Diana

AU - Kempton, Matthew

AU - Bhavsar, Vishal

AU - Arathimos, Ryan

AU - Coleman, Jonathan

AU - Valmaggia, Lucia

AU - Tognin, Stefania

AU - Modinos, Gemma

AU - Fusar-Poli, Paolo

AU - Quattrone, Diego

AU - Breen, Gerome

AU - Di Forti, Marta

AU - Morgan, Craig

AU - Lewis, Cathryn

AU - Hotopf, Matthew

AU - Mcguire, Philip

AU - Murray, Robin

AU - Vassos, Evangelos

PY - 2026/10/14

Y1 - 2026/10/14

N2 - Background: The psychosis continuum conceptualises psychotic phenomena as existing on a spectrum from subclinical experiences to psychotic disorders. Despite epidemiological and clinical evidence in support of this model, few studies have examined polygenic liability across the severity continuum: from subclinical experiences to first-episode psychosis. Aims: To map polygenic liability for schizophrenia, bipolar disorder, and major depressive disorder across the psychosis continuum. We hypothesized that schizophrenia polygenic scores (SCZ-PGS) would track phenotypic severity most closely across this continuum. Method: We harmonized data from five Southeast London cohorts (N=1,315; 860 European, 455 African ancestries) across four ordered groups indicative of different levels of phenotypic severity: controls (N=647), individuals with self-reported psychotic experiences (N=89), individuals at clinical high-risk (CHR) that did not convert to psychosis (N=124), and individuals with first-episode psychosis (FEP; N=455). We computed ancestry-specific polygenic scores for schizophrenia (SCZ), bipolar disorder (BD), and major depressive disorder (MDD), and compared these across groups with ordinal logistic regression. Results: In European ancestry participants, elevated SCZ-PGS (OR=1.72, p=4.57x10-15), BD-PGS (OR=1.56, p=1.03x10⁻¹⁰), and MDD-PGS (OR=1.44, p=4.86x10⁻⁸) were individually associated with increasing phenotypic severity. SCZ-PGS explained the largest variance (R²=0.084) across the psychosis continuum and showed pairwise differences between CHR and controls (β=0.32, p=0.027), and between FEP and CHR (β=0.38, p=0.017). Multivariable models, combining three PGS, outperformed univariable models (R²=0.105). Similar trends in SCZ-PGS across the psychosis continuum phenotype were seen in African ancestry participants, but only controls and FEP groups differed significantly (β=0.27, p=0.037). Conclusions: Our findings provide biological evidence supporting the psychosis continuum framework. In European ancestry, SCZ-PGS differences suggest that CHR who do not transition to psychosis have intermediate genetic vulnerability. Multivariable models, utilising all three PGS, explained additional variance compared to univariable ones, supporting transdiagnostic genetic liability. Improving PGS predictive power in African ancestry remains a priority.

AB - Background: The psychosis continuum conceptualises psychotic phenomena as existing on a spectrum from subclinical experiences to psychotic disorders. Despite epidemiological and clinical evidence in support of this model, few studies have examined polygenic liability across the severity continuum: from subclinical experiences to first-episode psychosis. Aims: To map polygenic liability for schizophrenia, bipolar disorder, and major depressive disorder across the psychosis continuum. We hypothesized that schizophrenia polygenic scores (SCZ-PGS) would track phenotypic severity most closely across this continuum. Method: We harmonized data from five Southeast London cohorts (N=1,315; 860 European, 455 African ancestries) across four ordered groups indicative of different levels of phenotypic severity: controls (N=647), individuals with self-reported psychotic experiences (N=89), individuals at clinical high-risk (CHR) that did not convert to psychosis (N=124), and individuals with first-episode psychosis (FEP; N=455). We computed ancestry-specific polygenic scores for schizophrenia (SCZ), bipolar disorder (BD), and major depressive disorder (MDD), and compared these across groups with ordinal logistic regression. Results: In European ancestry participants, elevated SCZ-PGS (OR=1.72, p=4.57x10-15), BD-PGS (OR=1.56, p=1.03x10⁻¹⁰), and MDD-PGS (OR=1.44, p=4.86x10⁻⁸) were individually associated with increasing phenotypic severity. SCZ-PGS explained the largest variance (R²=0.084) across the psychosis continuum and showed pairwise differences between CHR and controls (β=0.32, p=0.027), and between FEP and CHR (β=0.38, p=0.017). Multivariable models, combining three PGS, outperformed univariable models (R²=0.105). Similar trends in SCZ-PGS across the psychosis continuum phenotype were seen in African ancestry participants, but only controls and FEP groups differed significantly (β=0.27, p=0.037). Conclusions: Our findings provide biological evidence supporting the psychosis continuum framework. In European ancestry, SCZ-PGS differences suggest that CHR who do not transition to psychosis have intermediate genetic vulnerability. Multivariable models, utilising all three PGS, explained additional variance compared to univariable ones, supporting transdiagnostic genetic liability. Improving PGS predictive power in African ancestry remains a priority.

M3 - Article

SN - 0007-1250

JO - British journal of psychiatry

JF - British journal of psychiatry

ER -