Identification of TMEM106B as a Shared Potential Drug Target for Depression and Stroke Through Comprehensive Genetic Analyses

Abstract

Background: The coexistence of depression and stroke has long been observed; however, their intrinsic link has not been fully understood. We aimed to inform the importance of depression intervention as a primary prevention of stroke by investigating shared genetic etiology and causal relationship underlying depression and stroke.

Methods: Leveraging summary statistics from the hitherto largest genome-wide association studies (GWAS) in European-ancestry individuals for depression (N_case/N_control = 294,322/741,438) and stroke (N_case/N_control = 73,652/1,234,808), we performed cross-trait linkage-disequilibrium (LD) score regression and SUPERGNOVA to quantify global and local genetic correlations, cross-trait meta-analysis to identify shared genetic loci, transcriptome-wide association study (TWAS) to detect shared tissue-specific gene expression, and Mendelian randomization (MR) analysis to make causal inference between the two conditions.

Results: We observed a significant positive global genetic correlation between depression and stroke (rg = 0.18, p = 2.92 ×10⁻⁹). Partitioning the whole genome, we observed one genomic region (11q23.2) presenting a significant local genetic correlation. Cross-trait meta-analysis and TWAS identified two shared genetic loci (TMEM106B and FES) revealing potential shared biological mechanisms involving lysosome localization. MR identified a putative causal association of genetically predicted depression on stroke (odds ratio [OR] = 1.13, 95% confidence interval [CI] = 1.07−1.19, p = 1.12 ×10⁻⁵). A considerable proportion of this association was mediated through smoking initiation (proportion-mediated [PM] = 44.0%, 95% CI = 19.9%–68.1%, p = 3.42 ×10⁻⁴), hypertension (PM = 34.0%, 95% CI = 14.5%–53.5%, p = 6.46 ×10⁻⁴), type 2 diabetes (PM = 19.0%, 95% CI = 8.5%–29.5%, p = 3.78 ×10⁻⁴), and atrial fibrillation (PM = 10.9%, 95% CI = 0.7%–21.1%, p = 3.61 ×10⁻²), respectively. MR in the reverse direction identified a putative association of genetically predicted stroke on depression (OR = 1.05, 95% CI = 1.01−1.09, p = 1.73 ×10⁻²), which attenuated to nonsignificant when correcting for both correlated and uncorrelated pleiotropy (OR = 1.00, 95% CI = 0.98−1.03, p = 0.88). Drug target MR identified causal associations of genetically predicted TMEM106B level on depression (OR = 0.92, 95% CI = 0.90−0.94, p = 2.04 ×10⁻¹²) and stroke (OR = 0.90, 95% CI = 0.86−0.95, p = 3.53 ×10⁻⁵).

Conclusion: Our work highlights a shared genetic basis and a putative causal relationship between depression and stroke, providing novel insights into the primary prevention of stroke by depression intervention.