Genetic variants associated with psychiatric disorders are enriched at epigenetically active sites in lymphoid cells

Mary-Ellen Lynall (), Blagoje Soskic, James Hayhurst, Jeremy Schwartzentruber, Daniel F. Levey, Gita A. Pathak, Renato Polimanti, Joel Gelernter, Murray B. Stein, Gosia Trynka, Menna R. Clatworthy and Ed Bullmore
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Mary-Ellen Lynall: University of Cambridge
Blagoje Soskic: Wellcome Genome Campus
James Hayhurst: Open Targets, Wellcome Genome Campus
Jeremy Schwartzentruber: Wellcome Genome Campus
Daniel F. Levey: VA Connecticut Healthcare System
Gita A. Pathak: VA Connecticut Healthcare System
Renato Polimanti: VA Connecticut Healthcare System
Joel Gelernter: VA Connecticut Healthcare System
Murray B. Stein: VA San Diego Healthcare System
Gosia Trynka: Wellcome Genome Campus
Menna R. Clatworthy: University of Cambridge Department of Medicine
Ed Bullmore: University of Cambridge

Nature Communications, 2022, vol. 13, issue 1, 1-15

Abstract: Abstract Multiple psychiatric disorders have been associated with abnormalities in both the innate and adaptive immune systems. The role of these abnormalities in pathogenesis, and whether they are driven by psychiatric risk variants, remains unclear. We test for enrichment of GWAS variants associated with multiple psychiatric disorders (cross-disorder or trans-diagnostic risk), or 5 specific disorders (cis-diagnostic risk), in regulatory elements in immune cells. We use three independent epigenetic datasets representing multiple organ systems and immune cell subsets. Trans-diagnostic and cis-diagnostic risk variants (for schizophrenia and depression) are enriched at epigenetically active sites in brain tissues and in lymphoid cells, especially stimulated CD4+ T cells. There is no evidence for enrichment of either trans-risk or cis-risk variants for schizophrenia or depression in myeloid cells. This suggests a possible model where environmental stimuli activate T cells to unmask the effects of psychiatric risk variants, contributing to the pathogenesis of mental health disorders.

Date: 2022
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DOI: 10.1038/s41467-022-33885-7

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