The genetic overlap between major depressive disorder, white blood cell counts and interleukin 6
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...
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Elsevier
2025-04-01
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| Series: | Journal of Affective Disorders Reports |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2666915325000198 |
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| author | Erik D Wiström Kevin S O'Connell Elise Koch Piotr Jaholkowski Guy F.L. Hindley Nils Eiel Steen Pravesh Parekh Charge Consortium, Oleksandr Frei Nadine Parker Alexey Shadrin Srdjan Djurovic Anders Dale Ole A Andreassen Olav B Smeland |
| author_facet | Erik D Wiström Kevin S O'Connell Elise Koch Piotr Jaholkowski Guy F.L. Hindley Nils Eiel Steen Pravesh Parekh Charge Consortium, Oleksandr Frei Nadine Parker Alexey Shadrin Srdjan Djurovic Anders Dale Ole A Andreassen Olav B Smeland |
| author_sort | Erik D Wiström |
| collection | DOAJ |
| description | 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 (nmax = 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. Abbreviations: 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 |
| format | Article |
| id | doaj-art-cd728ca94d3b42dc98f35596036d02f4 |
| institution | OA Journals |
| issn | 2666-9153 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | Elsevier |
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| series | Journal of Affective Disorders Reports |
| spelling | doaj-art-cd728ca94d3b42dc98f35596036d02f42025-08-20T02:19:10ZengElsevierJournal of Affective Disorders Reports2666-91532025-04-012010088910.1016/j.jadr.2025.100889The genetic overlap between major depressive disorder, white blood cell counts and interleukin 6Erik D Wiström0Kevin S O'Connell1Elise Koch2Piotr Jaholkowski3Guy F.L. Hindley4Nils Eiel Steen5Pravesh Parekh6Charge Consortium, Oleksandr Frei7Nadine Parker8Alexey Shadrin9Srdjan Djurovic10Anders Dale11Ole A Andreassen12Olav B Smeland13Centre for Precision Psychiatry, Institute of Clinical Medicine, University of Oslo, Oslo, Norway, Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway; Corresponding authors at: Kirkeveien 166, 0424 Oslo, Norway.Centre for Precision Psychiatry, Institute of Clinical Medicine, University of Oslo, Oslo, Norway, Division of Mental Health and Addiction, Oslo University Hospital, Oslo, NorwayCentre for Precision Psychiatry, Institute of Clinical Medicine, University of Oslo, Oslo, Norway, Division of Mental Health and Addiction, Oslo University Hospital, Oslo, NorwayCentre for Precision Psychiatry, Institute of Clinical Medicine, University of Oslo, Oslo, Norway, Division of Mental Health and Addiction, Oslo University Hospital, Oslo, NorwayCentre for Precision Psychiatry, Institute of Clinical Medicine, University of Oslo, Oslo, Norway, Division of Mental Health and Addiction, Oslo University Hospital, Oslo, NorwayCentre for Precision Psychiatry, Institute of Clinical Medicine, University of Oslo, Oslo, Norway, Division of Mental Health and Addiction, Oslo University Hospital, Oslo, NorwayCentre for Precision Psychiatry, Institute of Clinical Medicine, University of Oslo, Oslo, Norway, Division of Mental Health and Addiction, Oslo University Hospital, Oslo, NorwayCentre for Precision Psychiatry, Institute of Clinical Medicine, University of Oslo, Oslo, Norway, Division of Mental Health and Addiction, Oslo University Hospital, Oslo, NorwayCentre for Precision Psychiatry, Institute of Clinical Medicine, University of Oslo, Oslo, Norway, Division of Mental Health and Addiction, Oslo University Hospital, Oslo, NorwayCentre for Precision Psychiatry, Institute of Clinical Medicine, University of Oslo, Oslo, Norway, Division of Mental Health and Addiction, Oslo University Hospital, Oslo, NorwayDepartment of Medical Genetics, Oslo University Hospital, Oslo, Norway, Department of Clinical Science, University of Bergen, Bergen, NorwayDepartment of Radiology, School of Medicine, University of California San Diego, La Jolla, California, USA, Center for Multimodal Imaging and Genetics, University of California San Diego, La Jolla, California, USA; Department of Cognitive Science, University of California San Diego, La Jolla, California, USA; Department of Psychiatry, University of California San Diego, La Jolla, California, USA; Department of Neuroscience, University of California San Diego, La Jolla, California, USACentre for Precision Psychiatry, Institute of Clinical Medicine, University of Oslo, Oslo, Norway, Division of Mental Health and Addiction, Oslo University Hospital, Oslo, NorwayCentre for Precision Psychiatry, Institute of Clinical Medicine, University of Oslo, Oslo, Norway, Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway; Corresponding authors at: Kirkeveien 166, 0424 Oslo, Norway.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 (nmax = 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. Abbreviations: 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 Studyhttp://www.sciencedirect.com/science/article/pii/S2666915325000198GWASDepressive etiologyLeukocyteInterleukin 6MoBa |
| spellingShingle | Erik D Wiström Kevin S O'Connell Elise Koch Piotr Jaholkowski Guy F.L. Hindley Nils Eiel Steen Pravesh Parekh Charge Consortium, Oleksandr Frei Nadine Parker Alexey Shadrin Srdjan Djurovic Anders Dale Ole A Andreassen Olav B Smeland The genetic overlap between major depressive disorder, white blood cell counts and interleukin 6 Journal of Affective Disorders Reports GWAS Depressive etiology Leukocyte Interleukin 6 MoBa |
| title | The genetic overlap between major depressive disorder, white blood cell counts and interleukin 6 |
| title_full | The genetic overlap between major depressive disorder, white blood cell counts and interleukin 6 |
| title_fullStr | The genetic overlap between major depressive disorder, white blood cell counts and interleukin 6 |
| title_full_unstemmed | The genetic overlap between major depressive disorder, white blood cell counts and interleukin 6 |
| title_short | The genetic overlap between major depressive disorder, white blood cell counts and interleukin 6 |
| title_sort | genetic overlap between major depressive disorder white blood cell counts and interleukin 6 |
| topic | GWAS Depressive etiology Leukocyte Interleukin 6 MoBa |
| url | http://www.sciencedirect.com/science/article/pii/S2666915325000198 |
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