RESUMEN
BACKGROUND: Educational attainment (EA) as a stable indicator of socioeconomic status has been confirmed to affect intracerebral hemorrhage (ICH), but the mechanism relating EA and ICH is still unknown. AIM: To explore the causal relationship between EA and ICH through a bidirectional and two-step Mendelian randomization (MR) study. METHODS: Using summary-level Genome-wide Association Study using GWAS data FROM CASES AND CONTROLS of European ancestry, we performed bidirectional and two-step MR analyses to explore the causal relationship between educational attainment and ICH to understand the mediating influence of risk factors in this process. We also carried out subgroup analysis according to the different sites (deep and lobar) of ICH. A set of sensitivity analyses were performed to test valid MR assumptions. RESULTS: Bidirectional MR analysis consistently demonstrated a unidirectional causal effect, revealing that higher EA had a protective influence on ICH. Each additional 1-standard deviation (SD) increase in genetically predicted years of schooling was associated with a reduced risk of all ICH (inverse variance weighted (IVW) OR: 0.381 [95 %CI: 0.264-0.549]), deep ICH (OR: 0.334 [95 %CI: 0.216-0.517]), and lobar ICH (OR: 0.422 [95 %CI: 0.261-0.682]). The mediating effect of EA on all ICH was mediated via systolic blood pressure (SBP) (6.93 % [1.20-13.45 %]) and body mass index (BMI) (17.87 % [3.92-34.64 %]), and the mediating effect of EA on deep ICH was also mediated via SBP (7.85 % [1.55-15.07 %]) and BMI (18.63 % [4.02-36.26 %]). CONCLUSION: This study provides robust genetic evidence for supporting the protective effect of EA on ICH risk, with further evidence that the effect of EA on deep ICH is partially mediated through hypertension and obesity. Further validation is needed to ascertain whether these findings are applicable to other racial or general population groups.
Asunto(s)
Hemorragia Cerebral , Escolaridad , Estudio de Asociación del Genoma Completo , Hipertensión , Análisis de la Aleatorización Mendeliana , Obesidad , Humanos , Hipertensión/genética , Hipertensión/fisiopatología , Hipertensión/diagnóstico , Hipertensión/epidemiología , Hemorragia Cerebral/genética , Factores de Riesgo , Medición de Riesgo , Obesidad/genética , Obesidad/epidemiología , Obesidad/diagnóstico , Predisposición Genética a la Enfermedad , Factores Protectores , Análisis de Mediación , Presión Sanguínea/genética , Fenotipo , Polimorfismo de Nucleótido Simple , Determinantes Sociales de la SaludRESUMEN
Background: Although observational studies have suggested a bidirectional relation between depression and intracranial aneurysms (IAs), their causal relations remain unclear. Thus we aimed to assess the causal association between depression and IAs. Methods: We conducted a bidirectional two-sample Mendelian randomization (MR) study using summary-level data from publicly available genome-wide association studies of depression (n = 500,199), IAs (n = 79,429), unruptured intracranial aneurysm (uIA) (n = 74,004), and subarachnoid hemorrhage (SAH) (n = 77,074). MR analyses included the inverse-variance weighted (IVW) method as the primary analytic, plus weighted-median, simple mode, weighted mode, MR-Egger, and MR PRESSO. Results: Genetically predicted depression was strongly positively related to IAs (odds ratio [OR] = 1.69, 95% confidence interval [CI] 1.19-2.39, p = 0.003), uIA (OR = 1.96, 95% CI 1.06-3.64, p = 0.032), and SAH (OR = 1.73, 95% CI 1.14-2.61, p = 0.009). Reverse MR analyses showed that while genetically predicted uIA was positively related to depression (OR = 1.02, 95% CI 1.00-1.05, p = 0.044), no causal relations were observed for either IAs or SAH for depression. Conclusion: Our findings provide evidence of a causal effect of depression on IAs, uIA, and SAH. For the reverse MR analyses, we found a causal impact of uIA on depression, but no causal influence of either IAs or SAH for depression.