TY - JOUR
T1 - Genetic association and drug target exploration of inflammation-related proteins with risk of major depressive disorder
AU - Sun, Wenxi
AU - Cao, Hongbao
AU - Liu, Dongming
AU - Baranova, Ancha
AU - Zhang, Fuquan
AU - Zhang, Xiaobin
N1 - Publisher Copyright:
© 2024 Elsevier Inc.
PY - 2025/1/10
Y1 - 2025/1/10
N2 - Background: In numerous observational studies, circulating inflammation-related proteins have been linked with major depressive disorder (MDD), yet the precise causal direction of this relationship remains unclear. This study aims to investigate the potential causal link between inflammation-related proteins and the risk of developing MDD. Methods: We utilized summary data from a genome-wide association study (GWAS) of 91 circulating inflammation-associated proteins in 14,824 individuals of European descent. Additionally, we incorporated findings from a substantial GWAS on MDD, which included 294,322 cases and 741,438 controls. Our analysis employed a two-sample bidirectional Mendelian randomization (MR) approach, with inverse variance weighting (IVW) as the primary method. We augmented this with two supplementary techniques (MR-Egger and weighted median approaches) to detect and address potential pleiotropy. Furthermore, to identify and evaluate possible drug targets, we conducted a thorough search within the Drug-Gene Interaction Database (DGIdb). Results: Analysis using MR unveiled significant and causative associations between genetically determined CASP-8 (odds ratio (OR): 0.97), CD40 (OR: 0.96), IL-18 (OR: 0.98), SLAMF1 (OR: 0.97), and uPA (OR: 0.98) with MDD. Conversely, reverse MR analysis indicated causal associations between MDD and CCL19 (OR: 1.15), HGF (OR: 1.15), IL-8 (OR: 1.10), IL-18 (OR: 1.11), IL20RA (OR: 1.12), TGFA (OR: 1.12) and TNFSF14 (OR: 1.16). Notably, a significant bidirectional causal link was observed between IL-18 and MDD. Gene-drug analysis identified CD40, HGF, IL-8, IL-18, SLAMF1, and TGFA as potential therapeutic targets. Conclusions: We've pinpointed causal links between inflammation-related proteins and MDD, offering compelling and innovative evidence to enhance our understanding of the inflammatory mechanisms involved in MDD and to investigate potential targets for anti-MDD medications.
AB - Background: In numerous observational studies, circulating inflammation-related proteins have been linked with major depressive disorder (MDD), yet the precise causal direction of this relationship remains unclear. This study aims to investigate the potential causal link between inflammation-related proteins and the risk of developing MDD. Methods: We utilized summary data from a genome-wide association study (GWAS) of 91 circulating inflammation-associated proteins in 14,824 individuals of European descent. Additionally, we incorporated findings from a substantial GWAS on MDD, which included 294,322 cases and 741,438 controls. Our analysis employed a two-sample bidirectional Mendelian randomization (MR) approach, with inverse variance weighting (IVW) as the primary method. We augmented this with two supplementary techniques (MR-Egger and weighted median approaches) to detect and address potential pleiotropy. Furthermore, to identify and evaluate possible drug targets, we conducted a thorough search within the Drug-Gene Interaction Database (DGIdb). Results: Analysis using MR unveiled significant and causative associations between genetically determined CASP-8 (odds ratio (OR): 0.97), CD40 (OR: 0.96), IL-18 (OR: 0.98), SLAMF1 (OR: 0.97), and uPA (OR: 0.98) with MDD. Conversely, reverse MR analysis indicated causal associations between MDD and CCL19 (OR: 1.15), HGF (OR: 1.15), IL-8 (OR: 1.10), IL-18 (OR: 1.11), IL20RA (OR: 1.12), TGFA (OR: 1.12) and TNFSF14 (OR: 1.16). Notably, a significant bidirectional causal link was observed between IL-18 and MDD. Gene-drug analysis identified CD40, HGF, IL-8, IL-18, SLAMF1, and TGFA as potential therapeutic targets. Conclusions: We've pinpointed causal links between inflammation-related proteins and MDD, offering compelling and innovative evidence to enhance our understanding of the inflammatory mechanisms involved in MDD and to investigate potential targets for anti-MDD medications.
KW - Bi-directional
KW - Gene-drug analysis
KW - GWAS
KW - Inflammatory proteins
KW - Major depressive disorder
KW - Mendelian randomization
UR - http://www.scopus.com/inward/record.url?scp=85206247254&partnerID=8YFLogxK
U2 - 10.1016/j.pnpbp.2024.111165
DO - 10.1016/j.pnpbp.2024.111165
M3 - Artículo
C2 - 39383931
AN - SCOPUS:85206247254
SN - 0278-5846
VL - 136
JO - Progress in Neuro-Psychopharmacology and Biological Psychiatry
JF - Progress in Neuro-Psychopharmacology and Biological Psychiatry
M1 - 111165
ER -