Department of Neurology, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China.
Department of Neurology, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China.
J Affect Disord. 2025 Jan 1;368:461-470. doi: 10.1016/j.jad.2024.09.061. Epub 2024 Sep 11.
Observational studies have suggested that mental disorders and cerebrovascular diseases (CVDs) may be risk factors for each other, but genetic evidence of a causal relationship is still lacking. We used Mendelian randomization (MR) studies to explore the causal relationship between mental disorders and CVDs from the genetic perspective.
To investigate the causal association between major depressive disorder (MDD), anxiety, attention deficit/hyperactivity disorder (ADHD), bipolar disorder and schizophrenia five kinds of mental disorders and CVDs using two-sample two-way MR analysis based on publicly available genome-wide association study (GWAS) data. We used as instrumental variables (IVs) single-nucleotide polymorphisms (SNPs) that were strongly associated with mental disorders and CVDs. IVW method was used as the main analysis method, and MR-IVW, MR-Egger methods, MR-PRESSO test, leave-one-out analysis and funnel plot were used for sensitivity analysis. We further conducted a meta-analysis to summarize the currently available MR analyses.
The results of forward MR study showed that there was a significant causal relationship between ADHD and AS (any stroke) (p = 0.001, OR (95%CI) =1.118 (1.047-1.195)), any ischemic stroke (AIS) (p = 0.004, OR (95%CI) =1.118(1.035-1.206)) and large artery stroke (LAS) (p = 0.026, OR (95%CI): 1.206(1.023-1.422)). No heterogeneity, pleiotropy and outliers were found in sensitivity analysis. The reverse MR study showed that IA (intracranial aneurysm) (p = 0.033, OR (95%CI) = 1.123(1.009-1.249)) and UIA (unruptured intracranial aneurysm) (p = 0.015, OR (95%CI) =1.040(1.008-1.074)) were risk factors for schizophrenia. Sensitivity analysis showed no pleiotropy, but there was heterogeneity. After excluding outliers, MR analysis showed that IA and UIA were still risk factors for schizophrenia. Our meta-analyses found statistical significance in causal relationships between ADHD and LAS (OR (95%CI) =1.18 (1.06-1.32), p = 0.003), IA and schizophrenia (OR (95%CI) =1.05 (1.02-1.08), p = 0.002) and UIA and schizophrenia (OR (95%CI) =1.03 (1.01-1.06), p = 0.010).
The MR study and meta-analysis suggest that genetically predicted ADHD is a risk factor for LAS, and IA and UIA increase the risk of schizophrenia. The result has implications for the development of feasible prevention strategies in the future.
观察性研究表明，精神障碍和脑血管疾病（CVDs）可能互为风险因素，但遗传证据仍存在不足。我们采用孟德尔随机化（MR）研究从遗传角度探讨精神障碍与 CVDs 之间的因果关系。
利用基于公开全基因组关联研究（GWAS）数据的两样本两向 MR 分析，探讨五种精神障碍（重度抑郁症、焦虑症、注意缺陷多动障碍、双相情感障碍和精神分裂症）与 CVDs 之间的因果关联。我们使用与精神障碍和 CVDs 密切相关的单核苷酸多态性（SNP）作为工具变量（IVs）。采用 IVW 法作为主要分析方法，并进行 MR-Egger 法、MR-PRESSO 检验、剔除一个样本分析和漏斗图进行敏感性分析。我们进一步进行了荟萃分析以总结目前可用的 MR 分析结果。
正向 MR 研究结果显示，ADHD 与任何中风（AS）（p=0.001，OR（95%CI）=1.118（1.047-1.195））、任何缺血性中风（AIS）（p=0.004，OR（95%CI）=1.118（1.035-1.206））和大动脉性中风（LAS）（p=0.026，OR（95%CI）：1.206（1.023-1.422））之间存在显著的因果关系。敏感性分析未发现异质性、多效性和异常值。反向 MR 研究显示，颅内动脉瘤（IA）（p=0.033，OR（95%CI）=1.123（1.009-1.249））和未破裂颅内动脉瘤（UIA）（p=0.015，OR（95%CI）=1.040（1.008-1.074））是精神分裂症的危险因素。敏感性分析显示无多效性，但存在异质性。剔除异常值后，MR 分析显示 IA 和 UIA 仍然是精神分裂症的危险因素。我们的荟萃分析发现 ADHD 与 LAS（OR（95%CI）=1.18（1.06-1.32），p=0.003）、IA 和精神分裂症（OR（95%CI）=1.05（1.02-1.08），p=0.002）和 UIA 与精神分裂症（OR（95%CI）=1.03（1.01-1.06），p=0.010）之间存在统计学意义的因果关系。
MR 研究和荟萃分析表明，遗传预测的 ADHD 是 LAS 的危险因素，IA 和 UIA 增加了精神分裂症的风险。该结果为未来制定可行的预防策略提供了依据。
