Evaluation of the Causal Effects of COVID‐19 on Alzheimer’s Disease: LD Score Regression Analysis and Mendelian Randomization Study
Jingchun Chen, Melika J. Cummings, Mark L. Zhang, Yimei Lu, Davis B Cammann, Jenifer Do, Jennifer J. Zheng- Psychiatry and Mental health
- Cellular and Molecular Neuroscience
- Geriatrics and Gerontology
- Neurology (clinical)
- Developmental Neuroscience
- Health Policy
- Epidemiology
Abstract
Background
COVID‐19 is an acute respiratory infection that is frequently followed by short‐ or long‐term neurological abnormalities, and may increase the risk of developing Alzheimer’s disease (AD). However, the genetic and biological mechanisms underlying this risk are poorly understood. Utilizing publicly available large genome‐wide association studies (GWAS), we explored the possible causal effects of three different COVID‐19 phenotypes on AD.
Method
COVID‐19 GWAS data from European cohorts were obtained from the Host Genetics Initiative website in its most recent release (HGI7‐EUR) with three phenotypes: 1) critically ill COVID‐19 (case/ctrl: 13,769/1,072,442); 2) hospitalized COVID‐19 (case/ctrl: 32,519/2,062,805); 3) regular COVID‐19 infection (case/ctrl: 2,475,240/12,597,856). European AD GWAS data were retrieved from Jansen et al.’s study (case/ctrl: 71,880/ 383,378). The linkage disequilibrium score regression (LDSC) and Mendelian randomization (MR) methods were used to analyze the genetic correlation and possible causal effects among the three COVID‐19 phenotypes and AD.
Result
LDSC indicated that AD had significant positive correlations with the critically ill COVID‐19 (FDR = 0.021, z = 2.45, rg = 0.224) and hospitalized COVID‐19 (FDR = 0.020, z = 2.71, rg = 0.241) phenotypes, but not regular COVID‐19 infection (FDR = 0.133). On the other hand, MR with the fixed‐effects inverse variance weighted method indicated that regular COVID‐19 had some causal effect on AD (P = 0.019, beta = 0.032). Marginal causal effects on AD were also found from critical COVID‐19 (P = 0.072, beta = 0.008) and hospitalized COVID‐19 (P = 0.082, beta = 0.013). In addition, MR with weighed mode method showed significant effects on AD from three COVID‐19 phenotypes (P = 0.040‐0.003), while MR‐Egger method did not show any significance between the two diseases.
Conclusion
Using LDSC and MR approaches, our preliminary data identified a genetic correlation between hospitalized and critically ill COVID‐19 phenotypes and AD, and possible causal effects on AD through genetic variants shared with standard COVID‐19 infection. With the continuing COVID‐19 epidemic and the high comorbidity and mortality of AD from COVID‐19 infection, our observations emphasize the urgency of understanding the overlapping genetic risk for the two diseases. Further studies might shed light on the long‐term neurological influence of COVID‐19 and further provide strategies for disease intervention against COVID‐19 and AD.