Polygenic liability for major depression, schizophrenia and bipolar disorder and treatment outcome across major psychiatric disorders
Abstract
Polygenic scores for major depression, schizophrenia and bipolar disorder have been related to treatment outcome. We analysed 4,007 patients of European ancestry from 7 cohorts: three with major depression (STAR*D, GSRD, PANDORA), two with bipolar disorder (STEP-BD, Barcelona) and two with schizophrenia (CATIE, HSRRm). The three scores were computed with PRS-CS from the latest Psychiatric Genomics Consortium studies. The primary outcome was good response or good course, harmonized from each cohorts instrument. Firth logistic regression within cohorts, adjusted for age, sex and ancestry components, was followed by random-effects pooling. A higher depression score was associated with lower odds of a good outcome (odds ratio per standard deviation 0.88, 95% confidence interval 0.79-0.99, p = .04; false discovery rate q = .11). The estimate remained below one in all 8 sensitivity analyses, including adjustment for baseline severity, and was negative in all 5 cohorts with a continuous improvement measure. The schizophrenia score pointed the same way (odds ratio 0.93, 95% confidence interval 0.85-1.01) with no heterogeneity. The bipolar score showed no pooled effect (odds ratio 0.97), and its direction differed by diagnosis. In pooled data spanning three diagnoses, higher polygenic liability to depression was nominally associated with a less favourable treatment outcome, although the association did not survive correction for multiple testing; schizophrenia liability showed a similar directional trend. These findings support further evaluation of disorder liability in multivariable models of treatment outcome.
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BibTeX
@misc{serretti2026polygenic,
title = {{Polygenic liability for major depression, schizophrenia and bipolar disorder and treatment outcome across major psychiatric disorders}},
author = {Alessandro Serretti and Daniel Souery and Siegfried Kasper and Gernot Fugger and Alexander Kautzky and Joseph Zohar and Stuart Montgomery and Panagiotis Ferentinos and Dan Rujescu and Raffaella Zanardi and Cristina Colombo and Francesco Benedetti and Diego Albani and Gianluigi Forloni and Stefano Barlati and Lisa Buson and Valentina Menesello and Paolo Martini and Rosana Carvalho Silva and Giulia Perusi and Gabriele Nibbio and Stefano Bignotti and PANDORA study group and Giovanni Battista Tura and Antonio Vita and Filippo Drago and Raffaele Ferri and Massimo Gennarelli and Alessandra Minelli and Eduard Vieta and Stefano Bonassi and Julien Mendlewicz},
howpublished = {medRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.22.26366267},
url = {https://www.medrxiv.org/content/10.64898/2026.10.22.26366267v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Polygenic liability for major depression, schizophrenia and bipolar disorder and treatment outcome across major psychiatric disorders
AU - Alessandro Serretti
AU - Daniel Souery
AU - Siegfried Kasper
AU - Gernot Fugger
AU - Alexander Kautzky
AU - Joseph Zohar
AU - Stuart Montgomery
AU - Panagiotis Ferentinos
AU - Dan Rujescu
AU - Raffaella Zanardi
AU - Cristina Colombo
AU - Francesco Benedetti
AU - Diego Albani
AU - Gianluigi Forloni
AU - Stefano Barlati
AU - Lisa Buson
AU - Valentina Menesello
AU - Paolo Martini
AU - Rosana Carvalho Silva
AU - Giulia Perusi
AU - Gabriele Nibbio
AU - Stefano Bignotti
AU - PANDORA study group
AU - Giovanni Battista Tura
AU - Antonio Vita
AU - Filippo Drago
AU - Raffaele Ferri
AU - Massimo Gennarelli
AU - Alessandra Minelli
AU - Eduard Vieta
AU - Stefano Bonassi
AU - Julien Mendlewicz
PY - 2026
DA - 2026/10/22
PB - medRxiv
DO - 10.64898/2026.10.22.26366267
UR - https://www.medrxiv.org/content/10.64898/2026.10.22.26366267v1
AB - Polygenic scores for major depression, schizophrenia and bipolar disorder have been related to treatment outcome. We analysed 4,007 patients of European ancestry from 7 cohorts: three with major depression (STAR*D, GSRD, PANDORA), two with bipolar disorder (STEP-BD, Barcelona) and two with schizophrenia (CATIE, HSRRm). The three scores were computed with PRS-CS from the latest Psychiatric Genomics Consortium studies. The primary outcome was good response or good course, harmonized from each cohorts instrument. Firth logistic regression within cohorts, adjusted for age, sex and ancestry components, was followed by random-effects pooling. A higher depression score was associated with lower odds of a good outcome (odds ratio per standard deviation 0.88, 95% confidence interval 0.79-0.99, p = .04; false discovery rate q = .11). The estimate remained below one in all 8 sensitivity analyses, including adjustment for baseline severity, and was negative in all 5 cohorts with a continuous improvement measure. The schizophrenia score pointed the same way (odds ratio 0.93, 95% confidence interval 0.85-1.01) with no heterogeneity. The bipolar score showed no pooled effect (odds ratio 0.97), and its direction differed by diagnosis. In pooled data spanning three diagnoses, higher polygenic liability to depression was nominally associated with a less favourable treatment outcome, although the association did not survive correction for multiple testing; schizophrenia liability showed a similar directional trend. These findings support further evaluation of disorder liability in multivariable models of treatment outcome.
ER -