Cholesterol-lowering statins, which are widely prescribed for treating and preventing cardiovascular diseases, have previously been reported to show anti-depressive properties. However, there is conflicting evidence on the association of statins with depression, and the molecular mechanisms that govern their potential anti-depressive effects remain largely veiled. We evaluated the anti-depressive activities of statins using a combined approach of transcriptomic signature matching and genetic

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... ociation analysis. We interrogated pre-compiled Connectivity Map (CMap) perturbational gene expression signatures and found that compounds with highly similar signatures to statins (average connectivity score > 90) were enriched for antidepressants (p < 1E-05). Genes perturbed in the same direction by both statins and antidepressants were significantly enriched for various immune pathways, while genes perturbed in the opposite direction were enriched for lipid metabolism pathways. Using publicly available expression quantitative trait loci (eQTL) and genome-wide association summary data, we performed Mendelian randomisation analysis to infer association of genetically predicted statin target inhibition with various depression, immune and disease traits. Genetically proxied HMGCR inhibition was significantly associated with extensive changes in immune cell traits, particularly platelet-related indices, and while we observed no genetic association between HMGCR expression and depression risk (p = 0.21), we found nominal association with depression-related worrying symptoms (p = 0.042). Our analyses provide genomic evidence for the association between statins and extensive alterations in immune-related processes, which have been linked to depression. Our findings carry clinical relevance, both for treating the increasing prevalence of individuals with comorbid cardiovascular diseases and depression, and for exploring the potential of repurposing statins for modulating depression symptoms.