Collective genomic segments with differential pleiotropic patterns between cognitive dimensions and psychopathology

Max Lam; Chia Yen Chen; W. David Hill; Charley Xia; Ruoyu Tian; Daniel F. Levey; Joel Gelernter; Murray B. Stein; Alexander S. Hatoum; Hailiang Huang; Anil K. Malhotra; Heiko Runz; Tian Ge; Todd Lencz

doi:10.1038/s41467-022-34418-y

Collective genomic segments with differential pleiotropic patterns between cognitive dimensions and psychopathology

Max Lam, Chia Yen Chen, W. David Hill, Charley Xia, Ruoyu Tian, Daniel F. Levey, Joel Gelernter, Murray B. Stein, Alexander S. Hatoum, Hailiang Huang, Anil K. Malhotra, Heiko Runz, Tian Ge, Todd Lencz^*

^*Corresponding author for this work

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

Abstract

Cognitive deficits are known to be related to most forms of psychopathology. Here, we perform local genetic correlation analysis as a means of identifying independent segments of the genome that show biologically interpretable pleiotropic associations between cognitive dimensions and psychopathology. We identify collective segments of the genome, which we call “meta-loci”, showing differential pleiotropic patterns for psychopathology relative to either cognitive task performance (CTP) or performance on a non-cognitive factor (NCF) derived from educational attainment. We observe that neurodevelopmental gene sets expressed during the prenatal-early childhood period predominate in CTP-relevant meta-loci, while post-natal gene sets are more involved in NCF-relevant meta-loci. Further, we demonstrate that neurodevelopmental gene sets are dissociable across CTP meta-loci with respect to their spatial distribution across the brain. Additionally, we find that GABA-ergic, cholinergic, and glutamatergic genes drive pleiotropic relationships within dissociable meta-loci.

Original language	English
Article number	6868
Journal	Nature Communications
Volume	13
Issue number	1
Early online date	11 Nov 2022
DOIs	https://doi.org/10.1038/s41467-022-34418-y
Publication status	Published - Dec 2022

Keywords / Materials (for Non-textual outputs)

cognitive neuroscience
genetic association study

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Lam, M., Chen, C. Y., Hill, W. D., Xia, C., Tian, R., Levey, D. F., Gelernter, J., Stein, M. B., Hatoum, A. S., Huang, H., Malhotra, A. K., Runz, H., Ge, T., & Lencz, T. (2022). Collective genomic segments with differential pleiotropic patterns between cognitive dimensions and psychopathology. Nature Communications, 13(1), Article 6868. https://doi.org/10.1038/s41467-022-34418-y

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abstract = "Cognitive deficits are known to be related to most forms of psychopathology. Here, we perform local genetic correlation analysis as a means of identifying independent segments of the genome that show biologically interpretable pleiotropic associations between cognitive dimensions and psychopathology. We identify collective segments of the genome, which we call “meta-loci”, showing differential pleiotropic patterns for psychopathology relative to either cognitive task performance (CTP) or performance on a non-cognitive factor (NCF) derived from educational attainment. We observe that neurodevelopmental gene sets expressed during the prenatal-early childhood period predominate in CTP-relevant meta-loci, while post-natal gene sets are more involved in NCF-relevant meta-loci. Further, we demonstrate that neurodevelopmental gene sets are dissociable across CTP meta-loci with respect to their spatial distribution across the brain. Additionally, we find that GABA-ergic, cholinergic, and glutamatergic genes drive pleiotropic relationships within dissociable meta-loci.",

keywords = "cognitive neuroscience, genetic association study",

author = "Max Lam and Chen, \{Chia Yen\} and Hill, \{W. David\} and Charley Xia and Ruoyu Tian and Levey, \{Daniel F.\} and Joel Gelernter and Stein, \{Murray B.\} and Hatoum, \{Alexander S.\} and Hailiang Huang and Malhotra, \{Anil K.\} and Heiko Runz and Tian Ge and Todd Lencz",

note = "Funding Information: The authors would like to thank the members of the Biogen Biobank team for analytic support. Research reported in this publication was supported by the National Institute of Mental Health of the National Institutes of Health under award number R01 MH117646 (T.L., Principal Investigator). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. W.D.H. and C.X. are supported by a Career Development Award from the Medical Research Council (MRC) [MR/T03052/1] for the project titled: “From genetic sequence to phenotypic consequence: genetic and environmental links between cognitive ability, socioeconomic position and health.”",

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doi = "10.1038/s41467-022-34418-y",

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AU - Chen, Chia Yen

AU - Hill, W. David

AU - Xia, Charley

AU - Tian, Ruoyu

AU - Levey, Daniel F.

AU - Gelernter, Joel

AU - Stein, Murray B.

AU - Hatoum, Alexander S.

AU - Huang, Hailiang

AU - Malhotra, Anil K.

AU - Runz, Heiko

AU - Ge, Tian

AU - Lencz, Todd

N1 - Funding Information: The authors would like to thank the members of the Biogen Biobank team for analytic support. Research reported in this publication was supported by the National Institute of Mental Health of the National Institutes of Health under award number R01 MH117646 (T.L., Principal Investigator). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. W.D.H. and C.X. are supported by a Career Development Award from the Medical Research Council (MRC) [MR/T03052/1] for the project titled: “From genetic sequence to phenotypic consequence: genetic and environmental links between cognitive ability, socioeconomic position and health.”

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N2 - Cognitive deficits are known to be related to most forms of psychopathology. Here, we perform local genetic correlation analysis as a means of identifying independent segments of the genome that show biologically interpretable pleiotropic associations between cognitive dimensions and psychopathology. We identify collective segments of the genome, which we call “meta-loci”, showing differential pleiotropic patterns for psychopathology relative to either cognitive task performance (CTP) or performance on a non-cognitive factor (NCF) derived from educational attainment. We observe that neurodevelopmental gene sets expressed during the prenatal-early childhood period predominate in CTP-relevant meta-loci, while post-natal gene sets are more involved in NCF-relevant meta-loci. Further, we demonstrate that neurodevelopmental gene sets are dissociable across CTP meta-loci with respect to their spatial distribution across the brain. Additionally, we find that GABA-ergic, cholinergic, and glutamatergic genes drive pleiotropic relationships within dissociable meta-loci.

AB - Cognitive deficits are known to be related to most forms of psychopathology. Here, we perform local genetic correlation analysis as a means of identifying independent segments of the genome that show biologically interpretable pleiotropic associations between cognitive dimensions and psychopathology. We identify collective segments of the genome, which we call “meta-loci”, showing differential pleiotropic patterns for psychopathology relative to either cognitive task performance (CTP) or performance on a non-cognitive factor (NCF) derived from educational attainment. We observe that neurodevelopmental gene sets expressed during the prenatal-early childhood period predominate in CTP-relevant meta-loci, while post-natal gene sets are more involved in NCF-relevant meta-loci. Further, we demonstrate that neurodevelopmental gene sets are dissociable across CTP meta-loci with respect to their spatial distribution across the brain. Additionally, we find that GABA-ergic, cholinergic, and glutamatergic genes drive pleiotropic relationships within dissociable meta-loci.

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ER -

Collective genomic segments with differential pleiotropic patterns between cognitive dimensions and psychopathology

Abstract

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