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. 2024 May 10:15:1377705.
doi: 10.3389/fpsyt.2024.1377705. eCollection 2024.

Causal relationship between genetic proxies for calcium channel blockers and the risk of depression: a drug-target Mendelian randomization study

Chaoyi Ye  1   2   3   4   5   6 , Tingjun Wang  1   2   4   5   6 , Huajun Wang  1   2   4   5   6 , Guili Lian  1   2   4   5   6 , Liangdi Xie  1   2   4   5   6
Affiliations

Causal relationship between genetic proxies for calcium channel blockers and the risk of depression: a drug-target Mendelian randomization study

Chaoyi Ye et al. Front Psychiatry. .

Abstract

Background: Calcium channel blockers (CCBs) are widely used in the clinical management of hypertension. Depression, a common comorbidity of hypertension, is an important issue in the management of hypertension. However, the impact of CCBs on depression risk remains controversial. We aim to investigate the causal effect of CCBs on depression through drug-target Mendelian randomization (MR) analysis.

Methods: To proxy CCBs, we utilized the genetic variations located in or around drug target genes that were related to systolic blood pressure (SBP). Coronary artery disease (CAD) served as the positive control outcome. Genetic summary data of SBP, CAD, and depression were obtained from genome-wide association studies (GWAS) based on European population. Inverse variance weighted (IVW) method was applied as the main analysis to estimate the causal effect. Cochran's Q test, MR-Egger intercept, MR pleiotropy residual sum and outlier (MR-PRESSO) and leave-one-out sensitivity analysis were used to test the robustness of the results. Meta-analysis was applied to further confirm whether causal relationships existed between CCBs and depression.

Results: The IVW results failed to reveal any causal relationship between genetic proxies for CCBs and depression (P > 0.05). Cochran's Q test showed no evidence of heterogeneity (P > 0.05). The MR-Egger intercept test suggested no evidence of directional pleiotropy, and the MR pleiotropy residual sum and outlier (MR-PRESSO) global test for horizontal pleiotropy was also not significant (P > 0.05). Leave-one-out analysis did not reveal any genetic variant that influenced the results. In addition, the meta-analysis further confirmed the absence of a causal relationship.

Conclusion: The present study indicates no association of genetic proxies for CCBs with depression. Further studies are necessary to provide definitive evidence.

Keywords: calcium channel blockers; depression; genome-wide association study; hypertension; mendelian randomization analysis.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Diagram of the study design. (A) The drug-target MR framework in this study. To verify the existence of a causal relationship, the following conditions are necessary: (1) the instrumental variables are not associated with confounding factors (dashed line), (2) the instrumental variables must be associated with the exposure factor (solid line), and (3) the instrumental variables are not directly related to the outcome (dashed line). (B) The overall study design and workflow. CAD, coronary artery disease; CCBs, calcium channel blockers; IVW, inverse variance weighted; MR, Mendelian randomization; MR-PRESSO, Mendelian randomization pleiotropy residual sum and outlier; SBP, systolic blood pressure; SNPs, single nucleotide polymorphisms.
Figure 2
Figure 2
Summary results of drug-target MR. CAD, coronary artery disease; OR, odds ratio; CI, confidence interval.
Figure 3
Figure 3
Meta-analysis was performed to assess the pooled effects of genetic proxied inhibition of (A) CACNA1D and (B) CACNB2 on depression. OR, odds ratio; CI, confidence interval.
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Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This work was supported by the National Natural Science Foundation of China under Grant NO. 82170355 and 82370351.