Genome-wide analysis identifies pleiotropic genes shared between severe mental disorders and biomarkers of cellular...

Severe mental disorders such as bipolar disorder (BD), major depressive disorder (MDD) and schizophrenia (SZ) are characterized by reduced life expectancy, premature mortality and alterations of aging biomarkers, leading to hypothesize that they might be associated with accelerated cellular aging. We quantified the genetic overlap between severe mental disorders and a comprehensive set of aging biomarkers including multivariate longevity and healthy aging (mvAge), brain age gap (BAG), leucocyte telomere length (gLTL), mitochondrial DNA copy number and epigenetic age acceleration (gEAA) using cutting-edge methods, and evaluated their functional enrichment and suitability as drug targets. All disorders were negatively correlated with mvAge. Further, MDD correlated negatively with gLTL and positively with gEAA. We identified several pleiotropic variants, with nine genes (AC068490.2, ASIC2, CNNM2, FURIN, GPM6A, HS6ST3, RP5-1043L13.1, SORCS3 and SP4) containing variants shared between aging biomarkers and all disorders. Functional analyses with summary-data-based Mendelian randomization showed that increased expression of the druggable gene CRHR1 in the prefrontal cortex was associated with increased risk of MDD and BAG measures. Our findings suggest that shared heritability might contribute to reduced longevity and healthy aging in severe mental disorders and identify pleiotropic genes involved in synaptic function and metabolic processes related to micronutrients such as folate and magnesium.