Abstract
Bipolar disorder (BD) has been previously associated with clinical signs of premature aging, including accelerated epigenetic aging in blood and brain, and a steeper age-related decline in cognitive function. However, the clinical drivers and cognitive correlates of epigenetic aging in BD are still unknown. We aimed to investigate the relationship between multiple measures of epigenetic aging acceleration with clinical, functioning, and cognitive outcomes in patients with BD and controls. Blood genome-wide DNA methylation levels were measured in BD patients (n = 153) and matched healthy controls (n = 50) with the Infinium MethylationEPIC BeadChip (Illumina). Epigenetic age estimates were calculated using an online tool, including the recently developed lifespan predictor GrimAge, and analyzed with generalized linear models controlling for demographic variables and blood cell proportions. BD was significantly associated with greater GrimAge acceleration (AgeAccelGrim, β=0.197, p = 0.009), and significant group-dependent interactions were found between AgeAccelGrim and blood cell proportions (CD4+ T-lymphocytes, monocytes, granulocytes, and B-cells). Within patients, higher AgeAccelGrim was associated with worse cognitive function in multiple domains (short-term affective memory (β=-0.078, p = 0.030), short-term non-affective memory (β=-0.088, p = 0.018), inhibition (β=0.064, p = 0.046), and problem solving (β=-0.067, p = 0.034)), age of first diagnosis with any mood disorder (β=-0.076, p = 0.039) or BD (β=-0.102, p = 0.016), as well as with current non-smoking status (β=-0.392, p < 0.001). Overall, our findings support the contribution of epigenetic factors to the aging-related cognitive decline and premature mortality reported in BD patients, with an important driving effect of smoking in this population.