Abstract
BACKGROUND: Immune dysregulation may contribute to the pathophysiology of major depressive disorder (MDD). Here we aimed to identify genetic architecture jointly associated with MDD, white blood cell (WBC) count and interleukin 6 (IL-6) levels. METHODS: Using genome-wide association studies summary statistics on MDD (330,173 cases and 727,595 controls), WBC counts (n (max) = 563,946) and IL-6 (n = 52,654), we performed linkage disequilibrium (LD) score regression, bivariate causal mixture model (MiXeR), conjunctional false discovery rate (conjFDR) and Mendelian randomization (MR) analyses. Additionally, we used an independent MDD dataset (9,582 cases and 84,670 controls) from the Norwegian Mother, Father and Child Cohort Study for polygenic risk score (PRS) analyses. FINDINGS: We found a significant positive genetic correlation (rg = 0.22) between MDD and IL-6. MiXeR estimates indicated substantial differences in the polygenicity of MDD (13.7K variants), WBC subgroups (0.8K-1.8K variants), and IL-6 (0.2K variants), with 10.1 %-31.4 % of the variants influencing WBC subgroups overlapping with MDD. We identified MDD risk loci shared with basophils (8), eosinophils (17), lymphocytes (23), monocytes (14), neutrophils (20), and total WBC counts (20), as well as two loci shared between MDD and IL-6, at conjFDR <0.05. PRS analysis showed a weak, but significantly increased risk for MDD dependent on monocyte count. LIMITATIONS: The analyses only included European ancestry samples, and the causal genes associated with the identified genetic loci were not experimentally validated. CONCLUSIONS: MDD shares genetic underpinnings with immune system components, which implicates immune- mediated pathways in the pathophysiology of MDD. However, this connection may only be relevant for a minority of patients.