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

Genetic Risk and Outcome of Psychosis (GROUP) Study; Psychosis Endophenotypes International Consortium (PEIC); Baihan Wang

doi:10.1093/schbul/sbad088

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

Genetic Risk and Outcome of Psychosis (GROUP) Study, Psychosis Endophenotypes International Consortium (PEIC), Baihan Wang^*

^*Corresponding author for this work

Univ London, Birkbeck University London, University College London, University of London Royal Veterinary College, University of London, St Georges University London, Imperial College London, Kings College London, Royal Holloway University London, Queen Mary University London, Div Populat Hlth Sci & Educ
Department of Neuroscience, Mental Health and Sensory Organs
Social Genetic and Developmental Psychiatry Centre
Psychology and Neuroscience
1Department of Hepatology, Imperial College London, London, UK. 2Institute of Liver Studies at King's College School of Medicine at King's College Hospital, London, UK. 3Institute of Human Health and Performance, University College London, London, UK. 4Department of Asthma Allergy and Lung Biology, King's College London, London, UK. 5Division of Critical Care Medicine, University of Alberta, Edmonton, Canada.
Department Basic and Clinical Neuroscience
The Maurice Wohl Clinical Neuroscience Institute
Expertise Center Movement Disorders Groningen, University Medical Center Groningen (UMCG), University of Groningen, Groningen, Netherlands
Department of Radiology, Maastricht University Medical Center, Maastricht, The Netherlands.
Fundació Docència i Recerca Mutua Terrassa
Institute of General Practice, Faculty of Medicine, University Hospital Cologne, University of Cologne, 50923 Cologne, Germany
Department of Cardiology, Division Heart & Lungs, University Medical Center Utrecht,Utrecht University, Utrecht, the Netherlands.; Department of Clinical Sciences, Faculty of Veterinary Medicine, Utrecht University, The Netherlands.
CIBERSAM, Valencia
Department of Psychiatry and Psychotherapy, Medical University of Vienna, Vienna, Austria. [email protected].; Center for Brain Research, Medical University of Vienna, Spitalgasse 4, 1090, Vienna, Austria. [email protected].
Radiology and Nuclear Medicine, Amsterdam Neuroscience, Amsterdam University Medical Centers, Location Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
Cardiff and Vale University Health Board
Department of Computational Biology - USR 3756 CNRS), Institut Pasteur, Paris, France; Department of Epidemiology, Harvard T. H. Chan School of Public Health, Harvard Medical School, Boston, MA, USA.
1] Genetic Epidemiology Unit, Department of Epidemiology, Erasmus University Medical Center, Rotterdam, the Netherlands. [2] Center for Medical Systems Biology, Leiden, the Netherlands. [3] Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, the Netherlands.
MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, United Kingdom; The Charles Bronfman Institute for Personalized Medicine, The Icahn School of Medicine at Mount Sinai, New York, New York, United States of America; The Department of Preventive Medicine, The Icahn School of Medicine at Mount Sinai, New York, New York, United States of America; The Genetics of Obesity and Related Metabolic Traits Program, The Icahn School of Medicine at Mount Sinai, New York, New York, United States of America; The Mindich Child Health and Development Institute, The Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.
Usher Institute, University of Edinburgh, Edinburgh, UK
Oxford Autoimmune Neurology Group, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK.; Department of Neurology, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.
Fundacion Argibide
Radiology, University Hospital Galway,Galway,Republic of Ireland.
St Magnus Hospital
Instituto de Biofísica e Engenharia Biomédica
Universidade Nova de Lisboa
North East London Foundation Trust. Goodmayes Hospital
Seoul National University
Aysel Sabuncu Brain Research Center
Institute of Psychiatry, Psychology and Neuroscience, King's College London and South London and Maudsley NHS Foundation Trust,UK and Department of Psychology,Bilkent University,Turkey.
National Magnetic Resonance Research Center (UMRAM)
Centre for Pain Research, University of Bath, Department of Experimental Psychology, University of Oxford, Department of Anaesthesiology & Pain Medicine, University of Washington, Clinical Health Psychology, University College London, and University College London Hospitals, and Psychology Department, Kings College London.
Zucker Hillside Hospital
National and Kapodistrian University of Athens
Yonsei University
Heidelberg Univ, Ruprecht Karl University Heidelberg, Mannheim Univ Hosp

Research output: Contribution to journal › Article › peer-review

1 Citation (Scopus)

Abstract

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.

CONCLUSIONS: 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 language	English
Pages (from-to)	1625-1636
Number of pages	12
Journal	Schizophrenia Bulletin
Volume	49
Issue number	6
Early online date	14 Aug 2023
DOIs	https://doi.org/10.1093/schbul/sbad088
Publication status	Published - Nov 2023

Keywords

Humans
Endophenotypes
Psychotic Disorders/genetics
Schizophrenia/genetics
Bipolar Disorder/genetics
Multifactorial Inheritance/genetics
Risk Factors
Genetic Predisposition to Disease

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@article{dc889a3e3f1b41cc859e7b66dd713a75,

title = "Psychosis Endophenotypes: A Gene-Set-Specific Polygenic Risk Score Analysis",

abstract = "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.CONCLUSIONS: 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.",

keywords = "Humans, Endophenotypes, Psychotic Disorders/genetics, Schizophrenia/genetics, Bipolar Disorder/genetics, Multifactorial Inheritance/genetics, Risk Factors, Genetic Predisposition to Disease",

author = "{Genetic Risk and Outcome of Psychosis (GROUP) Study} and {Psychosis Endophenotypes International Consortium (PEIC)} and Baihan Wang and Haritz Irizar and Thygesen, {Johan H} and Eirini Zartaloudi and Isabelle Austin-Zimmerman and Anjali Bhat and Jasmine Harju-Sepp{\"a}nen and Oliver Pain and Nick Bass and Vasiliki Gkofa and Alizadeh, {Behrooz Z} and {van Amelsvoort}, Therese and Arranz, {Maria J} and Stephan Bender and Wiepke Cahn and {Stella Calafato}, Maria and Benedicto Crespo-Facorro and {Di Forti}, Marta and Ina Giegling and {de Haan}, Lieuwe and Jeremy Hall and Mei-Hua Hall and {van Haren}, Neeltje and Conrad Iyegbe and Kahn, {Ren{\'e} S} and Eugenia Kravariti and Lawrie, {Stephen M} and Kuang Lin and Luykx, {Jurjen J} and Ignacio Mata and Colm McDonald and McIntosh, {Andrew M} and Murray, {Robin M} and Marco Picchioni and John Powell and Prata, {Diana P} and Dan Rujescu and Rutten, {Bart P F} and Madiha Shaikh and Simons, {Claudia J P} and Timothea Toulopoulou and Matthias Weisbrod and {van Winkel}, Ruud and Karoline Kuchenbaecker and Andrew McQuillin and Elvira Bramon",

note = "{\textcopyright} The Author(s) 2023. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center.",

year = "2023",

month = nov,

doi = "10.1093/schbul/sbad088",

language = "English",

volume = "49",

pages = "1625--1636",

journal = "Schizophrenia Bulletin",

issn = "0586-7614",

publisher = "Oxford University Press",

number = "6",

}

TY - JOUR

T1 - Psychosis Endophenotypes

T2 - A Gene-Set-Specific Polygenic Risk Score Analysis

AU - Genetic Risk and Outcome of Psychosis (GROUP) Study

AU - Psychosis Endophenotypes International Consortium (PEIC)

AU - Wang, Baihan

AU - Irizar, Haritz

AU - Thygesen, Johan H

AU - Zartaloudi, Eirini

AU - Austin-Zimmerman, Isabelle

AU - Bhat, Anjali

AU - Harju-Seppänen, Jasmine

AU - Pain, Oliver

AU - Bass, Nick

AU - Gkofa, Vasiliki

AU - Alizadeh, Behrooz Z

AU - van Amelsvoort, Therese

AU - Arranz, Maria J

AU - Bender, Stephan

AU - Cahn, Wiepke

AU - Stella Calafato, Maria

AU - Crespo-Facorro, Benedicto

AU - Di Forti, Marta

AU - Giegling, Ina

AU - de Haan, Lieuwe

AU - Hall, Jeremy

AU - Hall, Mei-Hua

AU - van Haren, Neeltje

AU - Iyegbe, Conrad

AU - Kahn, René S

AU - Kravariti, Eugenia

AU - Lawrie, Stephen M

AU - Lin, Kuang

AU - Luykx, Jurjen J

AU - Mata, Ignacio

AU - McDonald, Colm

AU - McIntosh, Andrew M

AU - Murray, Robin M

AU - Picchioni, Marco

AU - Powell, John

AU - Prata, Diana P

AU - Rujescu, Dan

AU - Rutten, Bart P F

AU - Shaikh, Madiha

AU - Simons, Claudia J P

AU - Toulopoulou, Timothea

AU - Weisbrod, Matthias

AU - van Winkel, Ruud

AU - Kuchenbaecker, Karoline

AU - McQuillin, Andrew

AU - Bramon, Elvira

PY - 2023/11

Y1 - 2023/11

N2 - 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.CONCLUSIONS: 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.

AB - 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.CONCLUSIONS: 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.

KW - Humans

KW - Endophenotypes

KW - Psychotic Disorders/genetics

KW - Schizophrenia/genetics

KW - Bipolar Disorder/genetics

KW - Multifactorial Inheritance/genetics

KW - Risk Factors

KW - Genetic Predisposition to Disease

U2 - 10.1093/schbul/sbad088

DO - 10.1093/schbul/sbad088

M3 - Article

C2 - 37582581

SN - 0586-7614

VL - 49

SP - 1625

EP - 1636

JO - Schizophrenia Bulletin

JF - Schizophrenia Bulletin

IS - 6

ER -

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

Abstract

Keywords

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