Abstract Background Observational studies have reported structural changes in the brains of patients with coronavirus disease 2019 (COVID-19); it remains unclear whether these associations are causal. Aim We evaluated the causal effects of COVID-19 susceptibility, hospitalization and severity on cortical structures. Design Mendelian randomization (MR) study. Methods Data on the different COVID-19 phenotypes were obtained from the latest large-scale genome-wide association study (R7) of the COVID-19 Host Genetics Initiative. Brain structure data, including cortical thickness (TH) and surface area (SA), were obtained from the ENIGMA Consortium. Additionally, we employed the round 5 dataset released in January 2021 as the validation cohort. The inverse-variance weighted (IVW) method was used as the primary analysis in MR. Sensitivity analyses were conducted to evaluate heterogeneity and pleiotropy. We performed enrichment analysis on the MR analyses that passed the sensitivity analysis filtering. Results After IVW and sensitivity analyses, we observed causal associations between COVID-19 susceptibility and rostral middle frontal SAw (P = 0.0308, β = −39.1236), cuneus THw (P = 0.0170, β = −0.0121), medial orbitofrontal THw (P = 0.0002, β = 0.0225), postcentral THw (P = 0.0217, β = −0.0106), temporal pole THw (P = 0.0077, β = 0.0359), medial orbitofrontal SAnw (P = 0.0106, β = −24.0397), medial orbitofrontal THnw (P = 0.0007, β = 0.0232), paracentral SAnw (P = 0.0483, β = −20.1442), rostral middle frontal SAnw (P = 0.0368, β = −81.9719) and temporal pole THnw (P = 0.0429, β = 0.0353). COVID-19 hospitalization had causal effects on medial orbitofrontal THw (P = 0.0053, β = 0.0063), postcentral THw (P = 0.0143, β = −0.0042), entorhinal THnw (P = 0.0142, β = 0.0142), medial orbitofrontal THnw (P = 0.0147, β = 0.0065) and paracentral SAnw (P = 0.0119, β = −7.9970). COVID-19 severity had causal effects on rostral middle frontal SAw (P = 0.0122, β = −11.8296), medial orbitofrontal THw (P = 0.0155, β = 0.0038), superior parietal THw (P = 0.0291, β = −0.0021), lingual SAnw (P = 0.0202, β = −11.5270), medial orbitofrontal THnw (P = 0.0290, β = 0.0039), paracentral SAnw (P = 0.0180, β = −5.7744) and pars triangularis SAnw (P = 0.0151, β = −5.4520). Conclusion Our MR results demonstrate a causal relationship between different COVID-19 phenotypes and cortical structures.

中文翻译：

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COVID-19 易感性、住院治疗和严重程度以及大脑皮质结构的风险：孟德尔随机研究

摘要 背景观察性研究报告了 2019 年冠状病毒病 (COVID-19) 患者大脑的结构变化；目前尚不清楚这些关联是否存在因果关系。 目的我们评估了 COVID-19 易感性、住院情况和严重程度对皮质结构的因果影响。 设计孟德尔随机化 (MR) 研究。 方法有关不同 COVID-19 表型的数据来自 COVID-19 宿主遗传学计划的最新大规模全基因组关联研究 (R7)。大脑结构数据，包括皮质厚度 (TH) 和表面积 (SA)，均从 ENIGMA 联盟获得。此外，我们使用 2021 年 1 月发布的第 5 轮数据集作为验证队列。逆方差加权（IVW）方法被用作 MR 的主要分析。进行敏感性分析以评估异质性和多效性。我们对通过敏感性分析过滤的 MR 分析进行了富集分析。 结果经过 IVW 和敏感性分析后，我们观察到了 COVID-19 易感性与头侧中额叶 SAw (P = 0.0308，β = -39.1236)、楔叶 THw (P = 0.0170，β = -0.0121)、内侧眶额 THw (P = 0.0002，β = 0.0225），中央后 THw（P = 0.0217，β = -0.0106），颞极 THw（P = 0.0077，β = 0.0359），内侧眶额 SAnw（P = 0.0106，β = -24.0397），内侧眶额 THnw （P = 0.0007，β = 0.0232），旁中央 SAnw（P = 0.0483，β = -20.1442），喙中额叶 SAnw（P = 0.0368，β = -81.9719）和颞极 THnw（P = 0.0429，β = 0.0353） 。COVID-19住院治疗对内侧眶额 THw (P = 0.0053, β = 0.0063)、中央后 THw (P = 0.0143, β = -0.0042)、内嗅 THnw (P = 0.0142, β = 0.0142)、内侧眶额 THnw ( P = 0.0147，β = 0.0065）和旁中心 SAnw（P = 0.0119，β = -7.9970）。COVID-19严重程度对头侧中额叶SAw（P = 0.0122，β = -11.8296）、内侧眶额THw（P = 0.0155，β = 0.0038）、上顶叶THw（P = 0.0291，β = -0.0021）、舌侧 SAnw (P = 0.0202, β = -11.5270)、内侧眶额 THnw (P = 0.0290, β = 0.0039)、旁中央 SAnw (P = 0.0180, β = -5.7744) 和三角部 SAnw (P = 0.0151, β = - 5.4520）。 结论我们的 MR 结果证明了不同的 COVID-19 表型和皮质结构之间的因果关系。