The Relationship Between Polygenic Risk Scores and Cognition in Schizophrenia

Alexander L. Richards; Antonio F. Pardinas; Aura Frizzati; Katherine E. Tansey; Amy J. Lynham; Peter Holmans; Sophie E. Legge; Jeanne E. Savage; Ingrid Agartz; Ole A. Andreassen; Gabriella A. M. Blokland; Aiden Corvin; Donna Cosgrove; Franziska Degenhardt; Srdjan Djurovic; Thomas Espeseth; Laura Ferraro; Charlotte Gayer-Anderson; Ina Giegling; Neeltje E. van Haren; Annette M. Hartmann; John J. Hubert; Erik G. Jonsson; Bettina Konte; Leonhard Lennertz; Loes M. Olde Loohuis; Ingrid Melle; Craig Morgan; Derek W. Morris; Robin M. Murray; Hakan Nyman; Roel A. Ophoff; Jim van Os; Tracey L. Petryshen; Diego Quattrone; Marcella Rietschel; Dan Rujescu; Bart P. F. Rutten; Fabian Streit; Jana Strohmaier; Patrick F. Sullivan; Kjetil Sundet; Michael Wagner; Valentina Escott-Price; Michael J. Owen; Gary Donohoe; Michael C. O'Donovan; James T. R. Walters; GRP Investigators; EUGEI WP2 Group; Schizophrenia Working Group of the Psychiatric Genomics Consortium

doi:10.1093/schbul/sbz061

The Relationship Between Polygenic Risk Scores and Cognition in Schizophrenia

Alexander L. Richards, Antonio F. Pardinas, Aura Frizzati, Katherine E. Tansey, Amy J. Lynham, Peter Holmans, Sophie E. Legge, Jeanne E. Savage, Ingrid Agartz, Ole A. Andreassen, Gabriella A. M. Blokland, Aiden Corvin, Donna Cosgrove, Franziska Degenhardt, Srdjan Djurovic, Thomas Espeseth, Laura Ferraro, Charlotte Gayer-Anderson, Ina Giegling, Neeltje E. van HarenAnnette M. Hartmann, John J. Hubert, Erik G. Jonsson, Bettina Konte, Leonhard Lennertz, Loes M. Olde Loohuis, Ingrid Melle, Craig Morgan, Derek W. Morris, Robin M. Murray, Hakan Nyman, Roel A. Ophoff, Jim van Os, Tracey L. Petryshen, Diego Quattrone, Marcella Rietschel, Dan Rujescu, Bart P. F. Rutten, Fabian Streit, Jana Strohmaier, Patrick F. Sullivan, Kjetil Sundet, Michael Wagner, Valentina Escott-Price, Michael J. Owen, Gary Donohoe, Michael C. O'Donovan, James T. R. Walters^*, GRP Investigators, EUGEI WP2 Group, Schizophrenia Working Group of the Psychiatric Genomics Consortium

^*Corresponding author for this work

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

Abstract

Background: Cognitive impairment is a clinically important feature of schizophrenia. Polygenic risk score (PRS) methods have demonstrated genetic overlap between schizophrenia, bipolar disorder (BD), major depressive disorder (MDD), educational attainment (EA), and IQ, but very few studies have examined associations between these PRS and cognitive phenotypes within schizophrenia cases. Methods: We combined genetic and cognitive data in 3034 schizophrenia cases from 11 samples using the general intelligence factor g as the primary measure of cognition. We used linear regression to examine the association between cognition and PRS for EA, IQ, schizophrenia, BD, and MDD. The results were then meta-analyzed across all samples. A genome-wide association studies (GWAS) of cognition was conducted in schizophrenia cases. Results: PRS for both population IQ (P = 4.39 x 10(-28)) and EA (P = 1.27 x 10(-26)) were positively correlated with cognition in those with schizophrenia. In contrast, there was no association between cognition in schizophrenia cases and PRS for schizophrenia (P = .39), BD (P = .51), or MDD (P = .49). No individual variant approached genome-wide significance in the GWAS. Conclusions: Cognition in schizophrenia cases is more strongly associated with PRS that index cognitive traits in the general population than PRS for neuropsychiatric disorders. This suggests the mechanisms of cognitive variation within schizophrenia are at least partly independent from those that predispose to schizophrenia diagnosis itself. Our findings indicate that this cognitive variation arises at least in part due to genetic factors shared with cognitive performance in populations and is not solely due to illness or treatment-related factors, although our findings are consistent with important contributions from these factors.

Original language	English
Pages (from-to)	336-344
Number of pages	9
Journal	Schizophrenia Bulletin
Volume	46
Issue number	2
DOIs	https://doi.org/10.1093/schbul/sbz061
Publication status	Published - Mar 2020

Keywords

psychiatry
genomics
intelligence
bioinformatics
GENOME-WIDE ASSOCIATION
COMMON VARIANTS
INTELLIGENCE
ABILITY
MEMORY
ENDOPHENOTYPES
HERITABILITY
METAANALYSIS
PERFORMANCE
CONSORTIUM

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Richards, A. L., Pardinas, A. F., Frizzati, A., Tansey, K. E., Lynham, A. J., Holmans, P., Legge, S. E., Savage, J. E., Agartz, I., Andreassen, O. A., Blokland, G. A. M., Corvin, A., Cosgrove, D., Degenhardt, F., Djurovic, S., Espeseth, T., Ferraro, L., Gayer-Anderson, C., Giegling, I., ... Schizophrenia Working Group of the Psychiatric Genomics Consortium (2020). The Relationship Between Polygenic Risk Scores and Cognition in Schizophrenia. Schizophrenia Bulletin, 46(2), 336-344. https://doi.org/10.1093/schbul/sbz061

@article{91f506156ae04bbdbfaa5dc896cef8f4,

title = "The Relationship Between Polygenic Risk Scores and Cognition in Schizophrenia",

abstract = "Background: Cognitive impairment is a clinically important feature of schizophrenia. Polygenic risk score (PRS) methods have demonstrated genetic overlap between schizophrenia, bipolar disorder (BD), major depressive disorder (MDD), educational attainment (EA), and IQ, but very few studies have examined associations between these PRS and cognitive phenotypes within schizophrenia cases. Methods: We combined genetic and cognitive data in 3034 schizophrenia cases from 11 samples using the general intelligence factor g as the primary measure of cognition. We used linear regression to examine the association between cognition and PRS for EA, IQ, schizophrenia, BD, and MDD. The results were then meta-analyzed across all samples. A genome-wide association studies (GWAS) of cognition was conducted in schizophrenia cases. Results: PRS for both population IQ (P = 4.39 x 10(-28)) and EA (P = 1.27 x 10(-26)) were positively correlated with cognition in those with schizophrenia. In contrast, there was no association between cognition in schizophrenia cases and PRS for schizophrenia (P = .39), BD (P = .51), or MDD (P = .49). No individual variant approached genome-wide significance in the GWAS. Conclusions: Cognition in schizophrenia cases is more strongly associated with PRS that index cognitive traits in the general population than PRS for neuropsychiatric disorders. This suggests the mechanisms of cognitive variation within schizophrenia are at least partly independent from those that predispose to schizophrenia diagnosis itself. Our findings indicate that this cognitive variation arises at least in part due to genetic factors shared with cognitive performance in populations and is not solely due to illness or treatment-related factors, although our findings are consistent with important contributions from these factors.",

keywords = "psychiatry, genomics, intelligence, bioinformatics, GENOME-WIDE ASSOCIATION, COMMON VARIANTS, INTELLIGENCE, ABILITY, MEMORY, ENDOPHENOTYPES, HERITABILITY, METAANALYSIS, PERFORMANCE, CONSORTIUM",

author = "Richards, {Alexander L.} and Pardinas, {Antonio F.} and Aura Frizzati and Tansey, {Katherine E.} and Lynham, {Amy J.} and Peter Holmans and Legge, {Sophie E.} and Savage, {Jeanne E.} and Ingrid Agartz and Andreassen, {Ole A.} and Blokland, {Gabriella A. M.} and Aiden Corvin and Donna Cosgrove and Franziska Degenhardt and Srdjan Djurovic and Thomas Espeseth and Laura Ferraro and Charlotte Gayer-Anderson and Ina Giegling and {van Haren}, {Neeltje E.} and Hartmann, {Annette M.} and Hubert, {John J.} and Jonsson, {Erik G.} and Bettina Konte and Leonhard Lennertz and Loohuis, {Loes M. Olde} and Ingrid Melle and Craig Morgan and Morris, {Derek W.} and Murray, {Robin M.} and Hakan Nyman and Ophoff, {Roel A.} and {van Os}, Jim and Petryshen, {Tracey L.} and Diego Quattrone and Marcella Rietschel and Dan Rujescu and Rutten, {Bart P. F.} and Fabian Streit and Jana Strohmaier and Sullivan, {Patrick F.} and Kjetil Sundet and Michael Wagner and Valentina Escott-Price and Owen, {Michael J.} and Gary Donohoe and O'Donovan, {Michael C.} and Walters, {James T. R.} and {GRP Investigators} and {EUGEI WP2 Group} and {Schizophrenia Working Group of the Psychiatric Genomics Consortium}",

note = "Funding Information: K. G. Jebsen Stiftelsen. The views expressed are those of the author(s) and not necessarily those of the National Health Service, the National Institute for Health Research or the Department of Health and Social Care. PF Sullivan reports the following potentially competing financial interests. Current: Lundbeck (advisory committee, grant recipient). Past 3 years: Pfizer (scientific advisory board), Element Genomics (consultation fee), and Roche (speaker reimbursement). CM Bulik (spouse) reports: Shire (grant recipient, Scientific Advisory Board member); Pearson and Walker (author, royalty recipient); OpenBiome (collaborator); uBiome (grant recipient/ collaborator); Recovery Record (collaborator). These interests are unrelated to this project. M.J.O., M.C.O., J.T.R.W. are supported by a collaborative research grant from Takeda. Takeda played no part in the conception, design, implementation, or interpretation of this study, which was completed before the funding award. No other conflicts of interest are reported. Funding Information: Cardiff University researchers were supported by Medical Research Council (MRC) Centre (G0800509) and Programme Grant (G0801418). This study was supported by the NIMH PGC grant (5U01MH109514-02). The EU-GEI Project was funded by the European Community{\textquoteright}s Seventh Framework Programme under grant agreement HEALTH-F2-2010–241909 (Project EU-GEI). This article represents independent research part funded by the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley National Health Service Foundation Trust and King{\textquoteright}s College London. Publisher Copyright: {\textcopyright} The Author(s) 2019.",

year = "2020",

month = mar,

doi = "10.1093/schbul/sbz061",

language = "English",

volume = "46",

pages = "336--344",

journal = "Schizophrenia Bulletin",

issn = "0586-7614",

publisher = "Oxford University Press",

number = "2",

}

Richards, AL, Pardinas, AF, Frizzati, A, Tansey, KE, Lynham, AJ, Holmans, P, Legge, SE, Savage, JE, Agartz, I, Andreassen, OA, Blokland, GAM, Corvin, A, Cosgrove, D, Degenhardt, F, Djurovic, S, Espeseth, T, Ferraro, L, Gayer-Anderson, C, Giegling, I, van Haren, NE, Hartmann, AM, Hubert, JJ, Jonsson, EG, Konte, B, Lennertz, L, Loohuis, LMO, Melle, I, Morgan, C, Morris, DW, Murray, RM, Nyman, H, Ophoff, RA, van Os, J, Petryshen, TL, Quattrone, D, Rietschel, M, Rujescu, D, Rutten, BPF, Streit, F, Strohmaier, J, Sullivan, PF, Sundet, K, Wagner, M, Escott-Price, V, Owen, MJ, Donohoe, G, O'Donovan, MC, Walters, JTR, GRP Investigators, EUGEI WP2 Group & Schizophrenia Working Group of the Psychiatric Genomics Consortium 2020, 'The Relationship Between Polygenic Risk Scores and Cognition in Schizophrenia', Schizophrenia Bulletin, vol. 46, no. 2, pp. 336-344. https://doi.org/10.1093/schbul/sbz061

TY - JOUR

T1 - The Relationship Between Polygenic Risk Scores and Cognition in Schizophrenia

AU - Richards, Alexander L.

AU - Pardinas, Antonio F.

AU - Frizzati, Aura

AU - Tansey, Katherine E.

AU - Lynham, Amy J.

AU - Holmans, Peter

AU - Legge, Sophie E.

AU - Savage, Jeanne E.

AU - Agartz, Ingrid

AU - Andreassen, Ole A.

AU - Blokland, Gabriella A. M.

AU - Corvin, Aiden

AU - Cosgrove, Donna

AU - Degenhardt, Franziska

AU - Djurovic, Srdjan

AU - Espeseth, Thomas

AU - Ferraro, Laura

AU - Gayer-Anderson, Charlotte

AU - Giegling, Ina

AU - van Haren, Neeltje E.

AU - Hartmann, Annette M.

AU - Hubert, John J.

AU - Jonsson, Erik G.

AU - Konte, Bettina

AU - Lennertz, Leonhard

AU - Loohuis, Loes M. Olde

AU - Melle, Ingrid

AU - Morgan, Craig

AU - Morris, Derek W.

AU - Murray, Robin M.

AU - Nyman, Hakan

AU - Ophoff, Roel A.

AU - van Os, Jim

AU - Petryshen, Tracey L.

AU - Quattrone, Diego

AU - Rietschel, Marcella

AU - Rujescu, Dan

AU - Rutten, Bart P. F.

AU - Streit, Fabian

AU - Strohmaier, Jana

AU - Sullivan, Patrick F.

AU - Sundet, Kjetil

AU - Wagner, Michael

AU - Escott-Price, Valentina

AU - Owen, Michael J.

AU - Donohoe, Gary

AU - O'Donovan, Michael C.

AU - Walters, James T. R.

AU - GRP Investigators

AU - EUGEI WP2 Group

AU - Schizophrenia Working Group of the Psychiatric Genomics Consortium

N1 - Funding Information: K. G. Jebsen Stiftelsen. The views expressed are those of the author(s) and not necessarily those of the National Health Service, the National Institute for Health Research or the Department of Health and Social Care. PF Sullivan reports the following potentially competing financial interests. Current: Lundbeck (advisory committee, grant recipient). Past 3 years: Pfizer (scientific advisory board), Element Genomics (consultation fee), and Roche (speaker reimbursement). CM Bulik (spouse) reports: Shire (grant recipient, Scientific Advisory Board member); Pearson and Walker (author, royalty recipient); OpenBiome (collaborator); uBiome (grant recipient/ collaborator); Recovery Record (collaborator). These interests are unrelated to this project. M.J.O., M.C.O., J.T.R.W. are supported by a collaborative research grant from Takeda. Takeda played no part in the conception, design, implementation, or interpretation of this study, which was completed before the funding award. No other conflicts of interest are reported. Funding Information: Cardiff University researchers were supported by Medical Research Council (MRC) Centre (G0800509) and Programme Grant (G0801418). This study was supported by the NIMH PGC grant (5U01MH109514-02). The EU-GEI Project was funded by the European Community’s Seventh Framework Programme under grant agreement HEALTH-F2-2010–241909 (Project EU-GEI). This article represents independent research part funded by the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley National Health Service Foundation Trust and King’s College London. Publisher Copyright: © The Author(s) 2019.

PY - 2020/3

Y1 - 2020/3

N2 - Background: Cognitive impairment is a clinically important feature of schizophrenia. Polygenic risk score (PRS) methods have demonstrated genetic overlap between schizophrenia, bipolar disorder (BD), major depressive disorder (MDD), educational attainment (EA), and IQ, but very few studies have examined associations between these PRS and cognitive phenotypes within schizophrenia cases. Methods: We combined genetic and cognitive data in 3034 schizophrenia cases from 11 samples using the general intelligence factor g as the primary measure of cognition. We used linear regression to examine the association between cognition and PRS for EA, IQ, schizophrenia, BD, and MDD. The results were then meta-analyzed across all samples. A genome-wide association studies (GWAS) of cognition was conducted in schizophrenia cases. Results: PRS for both population IQ (P = 4.39 x 10(-28)) and EA (P = 1.27 x 10(-26)) were positively correlated with cognition in those with schizophrenia. In contrast, there was no association between cognition in schizophrenia cases and PRS for schizophrenia (P = .39), BD (P = .51), or MDD (P = .49). No individual variant approached genome-wide significance in the GWAS. Conclusions: Cognition in schizophrenia cases is more strongly associated with PRS that index cognitive traits in the general population than PRS for neuropsychiatric disorders. This suggests the mechanisms of cognitive variation within schizophrenia are at least partly independent from those that predispose to schizophrenia diagnosis itself. Our findings indicate that this cognitive variation arises at least in part due to genetic factors shared with cognitive performance in populations and is not solely due to illness or treatment-related factors, although our findings are consistent with important contributions from these factors.

AB - Background: Cognitive impairment is a clinically important feature of schizophrenia. Polygenic risk score (PRS) methods have demonstrated genetic overlap between schizophrenia, bipolar disorder (BD), major depressive disorder (MDD), educational attainment (EA), and IQ, but very few studies have examined associations between these PRS and cognitive phenotypes within schizophrenia cases. Methods: We combined genetic and cognitive data in 3034 schizophrenia cases from 11 samples using the general intelligence factor g as the primary measure of cognition. We used linear regression to examine the association between cognition and PRS for EA, IQ, schizophrenia, BD, and MDD. The results were then meta-analyzed across all samples. A genome-wide association studies (GWAS) of cognition was conducted in schizophrenia cases. Results: PRS for both population IQ (P = 4.39 x 10(-28)) and EA (P = 1.27 x 10(-26)) were positively correlated with cognition in those with schizophrenia. In contrast, there was no association between cognition in schizophrenia cases and PRS for schizophrenia (P = .39), BD (P = .51), or MDD (P = .49). No individual variant approached genome-wide significance in the GWAS. Conclusions: Cognition in schizophrenia cases is more strongly associated with PRS that index cognitive traits in the general population than PRS for neuropsychiatric disorders. This suggests the mechanisms of cognitive variation within schizophrenia are at least partly independent from those that predispose to schizophrenia diagnosis itself. Our findings indicate that this cognitive variation arises at least in part due to genetic factors shared with cognitive performance in populations and is not solely due to illness or treatment-related factors, although our findings are consistent with important contributions from these factors.

KW - psychiatry

KW - genomics

KW - intelligence

KW - bioinformatics

KW - GENOME-WIDE ASSOCIATION

KW - COMMON VARIANTS

KW - INTELLIGENCE

KW - ABILITY

KW - MEMORY

KW - ENDOPHENOTYPES

KW - HERITABILITY

KW - METAANALYSIS

KW - PERFORMANCE

KW - CONSORTIUM

U2 - 10.1093/schbul/sbz061

DO - 10.1093/schbul/sbz061

M3 - Article

C2 - 31206164

SN - 0586-7614

VL - 46

SP - 336

EP - 344

JO - Schizophrenia Bulletin

JF - Schizophrenia Bulletin

IS - 2

ER -