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

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.