From the Department of Neurology (Z.Z., X.L., W.Z.), Nanjing Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University; Department of Neurology (M.W.), The First People's Hospital of Changzhou, The Third Affiliated Hospital of Soochow University, Jiangsu, China; and Department of Epidemiology and Biostatistics (D.G.), School of Public Health, St Mary's Hospital, Imperial College London, United Kingdom.
Neurology. 2024 Sep 10;103(5):e209776. doi: 10.1212/WNL.0000000000209776. Epub 2024 Aug 8.
Anxiety and depression have implications for ischemic stroke recovery. This study explored the association of genetically predicted anxiety and depression with functional outcome after ischemic stroke using Mendelian randomization (MR) approach.
Independent genetic variants associated with anxiety and depression at genome-wide significance level ( < 5 × 10) were obtained from large-scale genome-wide association studies (N = 1,306,354). Genetic results of poststroke outcome were obtained from Genetics of Ischemic Stroke Functional Outcome meta-analysis (N = 6,021). Three months after ischemic stroke event, the functional outcome was appraised with the modified Rankin Scale (mRS) score, and a mRS >2 was defined as worse functional outcome. Odds ratios (ORs) and 95% CIs are reported for the association of genetically predicted anxiety and depression with functional outcome after ischemic stroke. The inverse-variance weighted method was adopted to pool estimates. Alternative MR methods such as the weighted median and MR using the Robust Adjusted Profile Score were used as sensitivity analyses. The intercept of MR-Egger regression was also adopted to assess pleiotropy. The heterogeneity among variants was assessed by and statistics.
Genetic liability to depression was associated with worse functional outcome after stroke (mRS 3-6, OR 2.30; 95% CI 1.18-4.49, = 0.015). Sensitivity analyses produced consistent results. The bidirectional MR analysis indicates that poststroke outcome did not influence liability to depression (OR 1.01, 95% CI 0.99-1.03; = 0.436). By comparison, genetic liability to anxiety was not related with poststroke outcome (OR 1.03; 95% CI 0.71-1.50; = 0.869). Analyses in models without adjustment for stroke severity also indicated that genetic liability to depression was related with poor functional outcome after ischemic stroke (OR 2.54; 95% CI 1.41-4.58; = 0.002). No evidence of heterogeneity or directional pleiotropy was observed ( > 0.05).
Our MR study provides evidence to support detrimental effects of depression on ischemic stroke functional outcome. Future studies are warranted to explore whether clinical intervention on depression can ameliorate functional outcome after ischemic stroke.
焦虑和抑郁与缺血性脑卒中的恢复有关。本研究通过孟德尔随机化（MR）方法，探讨了遗传预测的焦虑和抑郁与缺血性脑卒中后功能结局的相关性。
从全基因组关联研究（N=1306354）中获得与焦虑和抑郁相关的全基因组显著水平（<5×10）的独立遗传变异。脑卒中后结局的遗传结果来自缺血性脑卒中功能结局的遗传学荟萃分析（N=6021）。缺血性脑卒中事件发生后 3 个月，采用改良 Rankin 量表（mRS）评分评估功能结局，mRS>2 定义为功能结局较差。报告了遗传预测的焦虑和抑郁与缺血性脑卒中后功能结局的相关性的比值比（OR）和 95%置信区间（CI）。采用逆方差加权法对估计值进行合并。作为敏感性分析，还采用加权中位数和稳健调整轮廓得分的 MR 方法。MR-Egger 回归的截距也用于评估偏倚。通过 2 和 统计量评估变异之间的异质性。
抑郁的遗传易感性与脑卒中后功能结局较差相关（mRS 3-6，OR 2.30；95%CI 1.18-4.49，=0.015）。敏感性分析结果一致。双向 MR 分析表明，脑卒中后结局不会影响抑郁的易感性（OR 1.01，95%CI 0.99-1.03；=0.436）。相比之下，焦虑的遗传易感性与脑卒中后结局无关（OR 1.03；95%CI 0.71-1.50；=0.869）。在未调整脑卒中严重程度的模型中进行的分析也表明，抑郁的遗传易感性与缺血性脑卒中后的不良功能结局相关（OR 2.54；95%CI 1.41-4.58；=0.002）。未观察到异质性或方向性偏倚的证据（>0.05）。
我们的 MR 研究提供了证据支持抑郁对缺血性脑卒中功能结局的不利影响。需要进一步的研究来探索是否对抑郁的临床干预可以改善缺血性脑卒中后的功能结局。
