Genetic variants associated with cross-disorder and disorder-specific risk for psychiatric disorders are enriched at epigenetically active sites in peripheral lymphoid cells

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 tested 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 used three independent epigenetic datasets representing multiple organ systems and immune cell subsets. Trans-diagnostic and cis-diagnostic risk variants (for schizophrenia and depression) were enriched at epigenetically active sites in brain tissues and in lymphoid cells (T, B and NK cells), especially stimulated CD4+ T cells. There was no evidence for enrichment of either trans-risk or cis-risk variants for schizophrenia or depression in myeloid cells. This suggests a model where stimuli (e.g. infection) activate T cells to unmask the effects of psychiatric risk variants, contributing to the pathogenesis of mental health disorders.