Multivariate genetic analysis of personality and cognitive traits reveals abundant pleiotropy

Guy Hindley; Alexey A. Shadrin; Dennis van der Meer; Nadine Parker; Weiqiu Cheng; Kevin S. O’Connell; Shahram Bahrami; Aihua Lin; Naz Karadag; Børge Holen; Thomas Bjella; Ian J. Deary; Gail Davies; W. David Hill; Jan Bressler; Sudha Seshadri; Chun Chieh Fan; Torill Ueland; Srdjan Djurovic; Olav B. Smeland; Oleksandr Frei; Anders M. Dale; Ole A. Andreassen

doi:10.1038/s41562-023-01630-9

Multivariate genetic analysis of personality and cognitive traits reveals abundant pleiotropy

Guy Hindley^*, Alexey A. Shadrin^*, Dennis van der Meer, Nadine Parker, Weiqiu Cheng, Kevin S. O’Connell, Shahram Bahrami, Aihua Lin, Naz Karadag, Børge Holen, Thomas Bjella, Ian J. Deary, Gail Davies, W. David Hill, Jan Bressler, Sudha Seshadri, Chun Chieh Fan, Torill Ueland, Srdjan Djurovic, Olav B. SmelandOleksandr Frei, Anders M. Dale, Ole A. Andreassen^*

^*Corresponding author for this work

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

Abstract

Personality and cognitive function are heritable mental traits whose genetic foundations may be distributed across interconnected brain functions. Previous studies have typically treated these complex mental traits as distinct constructs. We applied the ‘pleiotropy-informed’ multivariate omnibus statistical test to genome-wide association studies of 35 measures of neuroticism and cognitive function from the UK Biobank (n = 336,993). We identified 431 significantly associated genetic loci with evidence of abundant shared genetic associations, across personality and cognitive function domains. Functional characterization implicated genes with significant tissue-specific expression in all tested brain tissues and brain-specific gene sets. We conditioned independent genome-wide association studies of the Big 5 personality traits and cognitive function on our multivariate findings, boosting genetic discovery in other personality traits and improving polygenic prediction. These findings advance our understanding of the polygenic architecture of these complex mental traits, indicating a prominence of pleiotropic genetic effects across higher order domains of mental function such as personality and cognitive function.

Original language	English
Journal	Nature Human Behaviour
Early online date	26 Jun 2023
DOIs	https://doi.org/10.1038/s41562-023-01630-9
Publication status	E-pub ahead of print - 26 Jun 2023

Keywords / Materials (for Non-textual outputs)

genetic variation
human behaviour

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10.1038/s41562-023-01630-9

HindleyEtalNHB2023MultivariateGeneticAnalysisAccepted author manuscript, 1.06 MBLicence: Creative Commons: Attribution (CC-BY)

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Hindley, G., Shadrin, A. A., van der Meer, D., Parker, N., Cheng, W., O’Connell, K. S., Bahrami, S., Lin, A., Karadag, N., Holen, B., Bjella, T., Deary, I. J., Davies, G., Hill, W. D., Bressler, J., Seshadri, S., Fan, C. C., Ueland, T., Djurovic, S., ... Andreassen, O. A. (2023). Multivariate genetic analysis of personality and cognitive traits reveals abundant pleiotropy. Nature Human Behaviour. Advance online publication. https://doi.org/10.1038/s41562-023-01630-9

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title = "Multivariate genetic analysis of personality and cognitive traits reveals abundant pleiotropy",

abstract = "Personality and cognitive function are heritable mental traits whose genetic foundations may be distributed across interconnected brain functions. Previous studies have typically treated these complex mental traits as distinct constructs. We applied the {\textquoteleft}pleiotropy-informed{\textquoteright} multivariate omnibus statistical test to genome-wide association studies of 35 measures of neuroticism and cognitive function from the UK Biobank (n = 336,993). We identified 431 significantly associated genetic loci with evidence of abundant shared genetic associations, across personality and cognitive function domains. Functional characterization implicated genes with significant tissue-specific expression in all tested brain tissues and brain-specific gene sets. We conditioned independent genome-wide association studies of the Big 5 personality traits and cognitive function on our multivariate findings, boosting genetic discovery in other personality traits and improving polygenic prediction. These findings advance our understanding of the polygenic architecture of these complex mental traits, indicating a prominence of pleiotropic genetic effects across higher order domains of mental function such as personality and cognitive function.",

keywords = "genetic variation, human behaviour",

author = "Guy Hindley and Shadrin, {Alexey A.} and {van der Meer}, Dennis and Nadine Parker and Weiqiu Cheng and O{\textquoteright}Connell, {Kevin S.} and Shahram Bahrami and Aihua Lin and Naz Karadag and B{\o}rge Holen and Thomas Bjella and Deary, {Ian J.} and Gail Davies and Hill, {W. David} and Jan Bressler and Sudha Seshadri and Fan, {Chun Chieh} and Torill Ueland and Srdjan Djurovic and Smeland, {Olav B.} and Oleksandr Frei and Dale, {Anders M.} and Andreassen, {Ole A.}",

note = "We thank the research participants, employees and researchers of the UK Biobank, 23andMe, CHARGE and TOP for making this research possible. This work was partly performed on the TSD (Services for Sensitive Data) facilities, owned by the University of Oslo, operated and developed by the TSD service group at the University of Oslo, IT Department. Computations were also performed on resources provided by UNINETT Sigma2—the National Infrastructure for High Performance Computing and Data Storage in Norway. We gratefully acknowledge support from the American National Institutes of Health (NS057198 (O.A.A.), EB000790 (O.A.A.), 1R01MH124839 (K.O. and O.A.A.)), the Research Council of Norway (324499 (O.A.A.), 324252 (O.A.A.), 300309 (G.H. and N.P.), 273291 (O.A.A.), 223273 (O.A.A.), 248980 (O.A.A.)), the South-East Norway Regional Health Authority (2019-108 (O.A.A.), 2022-073 (O.A.A.)), European Economic Area and Norway grants (no. EEA-RO-NO-2018-0573 (A.A.S.), KG Jebsen Stiftelsen (SKGJ-MED-021 (O.A.A.) and the University of Oslo (B.H.)). This project has received funding from the European Union{\textquoteright}s Horizon 2020 research and innovation programme under grant agreement nos 847776 (O.A.A.) and 964874 (O.A.A.) and 801133 (W.C., N.P.) (Marie Sklodowska-Curie grant agreement). W.D.H. is supported by a Career Development Award from the Medical Research Council (MR/T030852/1). Infrastructure for the CHARGE Consortium is supported in part by the National Heart, Lung, and Blood Institute grant R01HL105756 (J.B., S.S.) and for the NeuroCHARGE Cognitive Working Group is supported in part through the National Institute on Aging grant R01AG033193 (J.B. and S.S.). I.J.D. and G.D. are with the Lothian Birth Cohorts group, which is supported by the Biotechnology and Biological Sciences Research Council and the Economic and Social Research Council (BB/W008793/1), Age UK (Disconnected Mind project), the Medical Research Council (MR/R024065/1) and the University of Edinburgh. The background vectors used in Fig. were created by freepik www.freepik.com and smart.servier.com . Freepik images were made by storyset and Freepik on Freepik. Servier Medical Art by Servier is licensed under a Creative Commons Attribution 3.0 Unported License ( https://creativecommons.org/licenses/by/3.0/ ).",

year = "2023",

month = jun,

day = "26",

doi = "10.1038/s41562-023-01630-9",

language = "English",

journal = "Nature Human Behaviour",

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Hindley, G, Shadrin, AA, van der Meer, D, Parker, N, Cheng, W, O’Connell, KS, Bahrami, S, Lin, A, Karadag, N, Holen, B, Bjella, T, Deary, IJ , Davies, G , Hill, WD, Bressler, J, Seshadri, S, Fan, CC, Ueland, T, Djurovic, S, Smeland, OB, Frei, O, Dale, AM & Andreassen, OA 2023, 'Multivariate genetic analysis of personality and cognitive traits reveals abundant pleiotropy', Nature Human Behaviour. https://doi.org/10.1038/s41562-023-01630-9

TY - JOUR

T1 - Multivariate genetic analysis of personality and cognitive traits reveals abundant pleiotropy

AU - Hindley, Guy

AU - Shadrin, Alexey A.

AU - van der Meer, Dennis

AU - Parker, Nadine

AU - Cheng, Weiqiu

AU - O’Connell, Kevin S.

AU - Bahrami, Shahram

AU - Lin, Aihua

AU - Karadag, Naz

AU - Holen, Børge

AU - Bjella, Thomas

AU - Deary, Ian J.

AU - Davies, Gail

AU - Hill, W. David

AU - Bressler, Jan

AU - Seshadri, Sudha

AU - Fan, Chun Chieh

AU - Ueland, Torill

AU - Djurovic, Srdjan

AU - Smeland, Olav B.

AU - Frei, Oleksandr

AU - Dale, Anders M.

AU - Andreassen, Ole A.

N1 - We thank the research participants, employees and researchers of the UK Biobank, 23andMe, CHARGE and TOP for making this research possible. This work was partly performed on the TSD (Services for Sensitive Data) facilities, owned by the University of Oslo, operated and developed by the TSD service group at the University of Oslo, IT Department. Computations were also performed on resources provided by UNINETT Sigma2—the National Infrastructure for High Performance Computing and Data Storage in Norway. We gratefully acknowledge support from the American National Institutes of Health (NS057198 (O.A.A.), EB000790 (O.A.A.), 1R01MH124839 (K.O. and O.A.A.)), the Research Council of Norway (324499 (O.A.A.), 324252 (O.A.A.), 300309 (G.H. and N.P.), 273291 (O.A.A.), 223273 (O.A.A.), 248980 (O.A.A.)), the South-East Norway Regional Health Authority (2019-108 (O.A.A.), 2022-073 (O.A.A.)), European Economic Area and Norway grants (no. EEA-RO-NO-2018-0573 (A.A.S.), KG Jebsen Stiftelsen (SKGJ-MED-021 (O.A.A.) and the University of Oslo (B.H.)). This project has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement nos 847776 (O.A.A.) and 964874 (O.A.A.) and 801133 (W.C., N.P.) (Marie Sklodowska-Curie grant agreement). W.D.H. is supported by a Career Development Award from the Medical Research Council (MR/T030852/1). Infrastructure for the CHARGE Consortium is supported in part by the National Heart, Lung, and Blood Institute grant R01HL105756 (J.B., S.S.) and for the NeuroCHARGE Cognitive Working Group is supported in part through the National Institute on Aging grant R01AG033193 (J.B. and S.S.). I.J.D. and G.D. are with the Lothian Birth Cohorts group, which is supported by the Biotechnology and Biological Sciences Research Council and the Economic and Social Research Council (BB/W008793/1), Age UK (Disconnected Mind project), the Medical Research Council (MR/R024065/1) and the University of Edinburgh. The background vectors used in Fig. were created by freepik www.freepik.com and smart.servier.com . Freepik images were made by storyset and Freepik on Freepik. Servier Medical Art by Servier is licensed under a Creative Commons Attribution 3.0 Unported License ( https://creativecommons.org/licenses/by/3.0/ ).

PY - 2023/6/26

Y1 - 2023/6/26

N2 - Personality and cognitive function are heritable mental traits whose genetic foundations may be distributed across interconnected brain functions. Previous studies have typically treated these complex mental traits as distinct constructs. We applied the ‘pleiotropy-informed’ multivariate omnibus statistical test to genome-wide association studies of 35 measures of neuroticism and cognitive function from the UK Biobank (n = 336,993). We identified 431 significantly associated genetic loci with evidence of abundant shared genetic associations, across personality and cognitive function domains. Functional characterization implicated genes with significant tissue-specific expression in all tested brain tissues and brain-specific gene sets. We conditioned independent genome-wide association studies of the Big 5 personality traits and cognitive function on our multivariate findings, boosting genetic discovery in other personality traits and improving polygenic prediction. These findings advance our understanding of the polygenic architecture of these complex mental traits, indicating a prominence of pleiotropic genetic effects across higher order domains of mental function such as personality and cognitive function.

AB - Personality and cognitive function are heritable mental traits whose genetic foundations may be distributed across interconnected brain functions. Previous studies have typically treated these complex mental traits as distinct constructs. We applied the ‘pleiotropy-informed’ multivariate omnibus statistical test to genome-wide association studies of 35 measures of neuroticism and cognitive function from the UK Biobank (n = 336,993). We identified 431 significantly associated genetic loci with evidence of abundant shared genetic associations, across personality and cognitive function domains. Functional characterization implicated genes with significant tissue-specific expression in all tested brain tissues and brain-specific gene sets. We conditioned independent genome-wide association studies of the Big 5 personality traits and cognitive function on our multivariate findings, boosting genetic discovery in other personality traits and improving polygenic prediction. These findings advance our understanding of the polygenic architecture of these complex mental traits, indicating a prominence of pleiotropic genetic effects across higher order domains of mental function such as personality and cognitive function.

KW - genetic variation

KW - human behaviour

UR - https://github.com/precimed/mostest/tree/mental

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U2 - 10.1038/s41562-023-01630-9

DO - 10.1038/s41562-023-01630-9

M3 - Article

AN - SCOPUS:85162925753

SN - 2397-3374

JO - Nature Human Behaviour

JF - Nature Human Behaviour

ER -

Multivariate genetic analysis of personality and cognitive traits reveals abundant pleiotropy

Abstract

Keywords / Materials (for Non-textual outputs)

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Other files and links

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The Lothian Birth Cohort 1936 Waves 6 and 7

From genetic sequence to phenotypic consequence: Genetic and environmental links between cognitive ability, socioeconomic position, and health

Disconnected Mind [Phase 2]

Cite this

Multivariate genetic analysis of personality and cognitive traits reveals abundant pleiotropy

Abstract

Keywords / Materials (for Non-textual outputs)

Access to Document

Other files and links

Fingerprint

Projects

The Lothian Birth Cohort 1936 Waves 6 and 7

From genetic sequence to phenotypic consequence: Genetic and environmental links between cognitive ability, socioeconomic position, and health

Disconnected Mind [Phase 2]

Cite this