Assessing the causal effects of type 2 diabetes and obesity-related traits on COVID-19 severity.

Background: Type 2 diabetes (T2D) and obesity-related traits are highly comorbid with coronavirus disease 2019 (COVID-19), but their causal relationships with disease severity remain unclear. While recent Mendelian randomization (MR) studies suggest a causal link between obesity-related traits and COVID-19 severity, findings regarding T2D are inconsistent, particularly when adjusting for body mass index (BMI). This study aims to clarify these relationships.

Methods: We applied various MR methods to assess the causal effects of BMI-adjusted T2D (T2DadjBMI) and obesity-related traits (BMI, waist circumference, and waist-hip ratio) on COVID-19 severity. Genetic instruments were obtained from large-scale genome-wide association studies (GWAS), including 898K participants for T2D and 2M for COVID-19 severity. To address potential bias from sample overlap, we conducted large-scale simulations comparing MR results from overlapping and independent samples.

Results: Our MR analysis identified a significant causal relationship between T2DadjBMI and increased COVID-19 severity (OR = 1.057, 95% CI = 1.012-1.105). Obesity-related traits were also causally associated with COVID-19 severity. Simulations confirmed that MR results remained robust to sample overlap, demonstrating consistency between overlapping and independent datasets.

Conclusions: These findings highlight the causal role of T2D and obesity-related traits in COVID-19 severity, emphasizing the need for targeted prevention and management strategies for high-risk populations. The robustness of our MR analysis, even in the presence of sample overlap, strengthens the reliability of these causal inferences.