The genetic overlap between major depressive disorder, white blood cell counts and interleukin 6
Year: 2025
Type: article
Study design: Observational Study
Abstract: • Immune dysregulation may contribute to major depressive disorder. • We evaluated genetic overlap with wite white blood cell count and interleukin 6. • Major depressive disorder shares genetic loci with these immunological traits. • This genetic overlap represents only a minority of variants affecting depression risk. 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. 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. 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. The analyses only included European ancestry samples, and the causal genes associated with the identified genetic loci were not experimentally validated. 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. MDD, major depressive disorder; White blood cell, WBC; MiXeR , bivariate causal mixture model; conjFDR, conjunctional false discovery rate; condFDR, conditional FDR; LD linkage disequilibrium; PRS, polygenic risk score; MoBa, Norwegian Mother, Father and Child Cohort Study
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $2,630
Funders: Stiftelsen Kristian Gerhard Jebsen, Trond Mohn stiftelse, Helse- og Omsorgsdepartementet, Haridus- ja Teadusministeerium, Universitetet i Bergen, Universitetet i Oslo, Norges Forskningsråd, Novo Nordisk Fonden, National Institutes of Health, European Research Council, Helse Sør-Øst RHF, EEA Grants, Horizon 2020, ULB Center for Diabetes Research, Norwegian Institute of Public Health, National Institute on Aging, National Heart, Lung, and Blood Institute, National Institute of Mental Health, National Institute on Drug Abuse, H2020 Marie Skłodowska-Curie Actions
Awards: G1300865376, G1420817852, G1470873464, G1510635755, G2455682238, G2498202452, G268108513, G3096137445, G3433676821, G3761261155, SCIENTIA-FELLOWS II: International Postdoctoral Fellowship Programme, G5479941350, G57285414, G6517481153, G7729610089, G7780503925, G9000052098, G9000112882, G9000318151, 3/7 Psychiatric Genomics Consortium: Advancing Discovery and Impact, OTA-21-015A Post-Acute Sequelae of SARS-CoV-2 Infection Initiative: NYU Langone Health Clinical Science Core, Data Resource Core, and PASC Biorepository Core
OpenAlex ID: W4407602812