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 and Todd Lencz ()
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Max Lam: The Zucker Hillside Hospital, Northwell
Chia-Yen Chen: Translational Biology, Research and Development, Biogen Inc
W. David Hill: University of Edinburgh
Charley Xia: University of Edinburgh
Ruoyu Tian: Computational Biology and Human Genetics, Dewpoint Therapeutics
Daniel F. Levey: Yale University School of Medicine
Joel Gelernter: Yale University School of Medicine
Murray B. Stein: VA San Diego Healthcare System
Alexander S. Hatoum: Washington University in St. Louis Medical School
Hailiang Huang: Broad Institute of MIT and Harvard
Anil K. Malhotra: The Zucker Hillside Hospital, Northwell
Heiko Runz: Translational Biology, Research and Development, Biogen Inc
Tian Ge: Broad Institute of MIT and Harvard
Todd Lencz: The Zucker Hillside Hospital, Northwell

Nature Communications, 2022, vol. 13, issue 1, 1-22

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-34418-y

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