Psychosis Endophenotypes: A Gene-Set-Specific Polygenic Risk Score Analysis

BH Wang*, Genetic Risk and Outcome of Psychosis (GROUP) investigators, Psychosis Endophenotypes International Consortium, H Irizar, JH Thygesen, E Zartaloudi, I Austin-Zimmerman, A Bhat, J Harju-Seppaenen, O Pain, N Bass, V Gkofa, BZ Alizadeh, T van Amelsvoort, MJ Arranz, S Bender, W Cahn, MS Calafato, B Crespo-Facorro, M Di FortiI Giegling, L de Haan, J Hall, MH Hall, N van Haren, C Iyegbe, RS Kahn, E Kravariti, SM Lawrie, K Lin, JJ Luykx, I Mata, C McDonald, AM McIntosh, RM Murray, M Picchioni, J Powell, DP Prata, D Rujescu, BPF Rutten, M Shaikh, CJP Simons, T Toulopoulou, M Weisbrod, R van Winkel, K Kuchenbaecker, A McQuillin, E Bramon*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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Background and Hypothesis:

Endophenotypes can help to bridge the gap between psychosis and its genetic predispositions, but their underlying mechanisms remain largely unknown. This study aims to identify biological mechanisms that are relevant to the endophenotypes for psychosis, by partitioning polygenic risk scores into specific gene sets and testing their associations with endophenotypes.

Study Design:

We computed polygenic risk scores for schizophrenia and bipolar disorder restricted to brain-related gene sets retrieved from public databases and previous publications. Three hundred and seventy-eight gene-set-specific polygenic risk scores were generated for 4506 participants. Seven endophenotypes were also measured in the sample. Linear mixed-effects models were fitted to test associations between each endophenotype and each gene-set-specific polygenic risk score.

Study Results:

After correction for multiple testing, we found that a reduced P300 amplitude was associated with a higher schizophrenia polygenic risk score of the forebrain regionalization gene set (mean difference per SD increase in the polygenic risk score: −1.15 µV; 95% CI: −1.70 to −0.59 µV; P = 6 × 10−5). The schizophrenia polygenic risk score of forebrain regionalization also explained more variance of the P300 amplitude (R2 = 0.032) than other polygenic risk scores, including the genome-wide polygenic risk scores.


Our finding on reduced P300 amplitudes suggests that certain genetic variants alter early brain development thereby increasing schizophrenia risk years later. Gene-set-specific polygenic risk scores are a useful tool to elucidate biological mechanisms of psychosis and endophenotypes, offering leads for experimental validation in cellular and animal models.
Original languageEnglish
Pages (from-to)1625-1636
Number of pages12
JournalSchizophrenia Bulletin
Issue number6
Early online date14 Aug 2023
Publication statusPublished - 1 Nov 2023

Bibliographical note

Publisher Copyright:
© 2023 The Author(s). Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center.


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