A genome-wide cross-trait analysis highlights the shared genetic structure between COVID-19 and Alzheimer's disease
Authors: Shizheng Qiu, Yang Hu, Liang Cheng
Journal: Journal of Infection (2021)

We read with interest the recently published research in Journal of Infection by Yang et al. who reported the higher mortality of COVID-19 patients with dementia compared with COVID-19 patients without dementia (effect estimate = 1.84, 95% CI: 1.57–2.16).1Yang H. Liang X. Hou H. Xu J. Shi L. Wang Y. The association of dementia with COVID-19 mortality: evidence based on adjusted effect estimates.J Infect. 2021; 82 (MayPubMed PMID: 33582205. Pubmed Central PMCID: PMC7879026. Epub 2021/02/15): e6-e10Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar Meanwhile, patients recovering from COVID-19 had a more severe burden of cognitive impairment, suggesting the potential risk of Alzheimer's disease.2Al-Aly Z. Xie Y. Bowe B. High-dimensional characterization of post-acute sequelae of COVID-19.Nature. 2021; 594 (JunPubMed PMID: 33887749. Epub 2021/04/23): 259-264Crossref PubMed Scopus (792) Google Scholar Although growing evidences indicate the potential genetic overlap between Alzheimer's disease and COVID-19, the genetic association degree and the shared genetic structure region between the two diseases remain unknown.3Lim K.H. Yang S. Kim S.H. Joo J.Y. Elevation of ACE2 as a SARS-CoV-2 entry receptor gene expression in Alzheimer's disease.J Infect. 2020; 81 (Sepe33-e4. PubMed PMID: 32619698. Pubmed Central PMCID: PMC7834154. Epub 2020/07/04)Abstract Full Text Full Text PDF Scopus (44) Google Scholar In this study, we aim to clarify the following three questions: (Ⅰ) Does the genetic association exist between COVID-19 and Alzheimer's disease? (Ⅱ) Where is the shared genetic region between COVID-19 and Alzheimer's disease? (Ⅲ) Is there a causal relationship between COVID-19 and Alzheimer's disease? In order to answer these questions, we obtained two large-scale genome-wide association studies (GWAS) summary statistics of Alzheimer's disease and COVID-19, respectively from International Genomics of Alzheimer's Project (IGAP) and COVID-19 Host Genetics Initiative.4Initiative C.H.G.Mapping the human genetic architecture of COVID-19.Nature. 2021; (Jul 8PubMed PMID: 34237774. Epub 2021/07/09, https://www.nature.com/articles/s41586-021-03767-x)Google Scholar,5Kunkle B.W. Grenier-Boley B. Sims R. Bis J.C. Damotte V. Naj A.C. et al.Genetic meta-analysis of diagnosed Alzheimer's disease identifies new risk loci and implicates abeta, tau, immunity and lipid processing.Nat Genet. 2019; 51 (MarPubMed PMID: 30820047. Pubmed Central PMCID: PMC6463297. Epub 2019/03/02): 414-430Crossref PubMed Scopus (1501) Google Scholar All the participants were of European descent. In stage 1, we evaluated genetic correlation between Alzheimer's disease and COVID-19 using linkage disequilibrium score (LDSC) regression analysis.6Bulik-Sullivan B. Finucane H.K. Anttila V. Gusev A. Day F.R. Loh P.R. et al.An atlas of genetic correlations across human diseases and traits.Nat Genet. 2015; 47 (NovPubMed PMID: 26414676. Pubmed Central PMCID: PMC4797329. Epub 2015/09/29): 1236-1241Crossref PubMed Scopus (2129) Google Scholar From an overall point of view, the genetic association seemed to have only suggestive significance (rg = 0.1048, P = 0.0782). In stage 2, We divided the gene components into 1703 LD-independent segments and calculated local genetic correlation of each segment, respectively using HESS (heritability estimation from summary statistics) 1Add reference: Shi HWB, Mancuso N, Spendlove S, Pasaniuc B. Local Genetic Correlation Gives Insights into the Shared Genetic Architecture of Complex Traits. Am J Hum Genet. 2017 Nov 2;101(5):737-51.. Chr19:44,744,108–46,102,697, containing several known Alzheimer's disease susceptibility loci, was the shared genetic region of Alzheimer's disease and COVID-19 (P = 4.38E-04). In chr19:44,744,108–46,102,697, APOE and APOC1 have been proven to be enriched in certain immune cells or tissues of COVID-19 patients and mediate the infection of SARS-CoV2 in neurons and astrocytes.7Shaath H. Vishnubalaji R. Elkord E. Alajez N.M. Single-cell transcriptome analysis highlights a role for neutrophils and inflammatory macrophages in the pathogenesis of severe COVID-19.Cells. 2020; 9 (Oct 29PubMed PMID: 33138195. Pubmed Central PMCID: PMC7693119. Epub 2020/11/04)2374Crossref Scopus (128) Google Scholar,8Wang C. Zhang M. Garcia G. Tian E. Cui Q. Chen X. et al.ApoE-isoform-dependent SARS-CoV-2 neurotropism and cellular response.Cell Stem Cell. 2021; 28 (Feb 4e5. PubMed PMID: 33450186. Pubmed Central PMCID: PMC7832490. Epub 2021/01/16): 331-342Abstract Full Text Full Text PDF PubMed Scopus (145) Google Scholar In stage 3, we performed a bidirectional two-sample Mendelian randomization (MR) analysis to reveal the causality between Alzheimer's disease and COVID-19.9Hemani G. Zheng J. Elsworth B. Wade K.H. Haberland V. Baird D. et al.The MR-base platform supports systematic causal inference across the human phenome.Elife. 2018; 7 (May 30PubMed PMID: 29846171. Pubmed Central PMCID: PMC5976434. Epub 2018/05/31)e34408Crossref PubMed Scopus (2898) Google Scholar When Alzheimer's disease was used as exposure and COVID-19 as outcome, 18 genetic variants were used as instrumental variables to carry out MR analysis. Inverse variance weighted (IVW) method showed a higher risk of COVID-19 for Alzheimer's disease patients (OR = 1.06, 95% CI: 1.00–1.12, P = 0.042) (Table 1). However, reverse MR found no evidence that COVID-19 led to Alzheimer's disease (P = 0.202).Table 1Five main methods to perform MR analysis between Alzheimer's disease and COVID-19.MethodbMethod→MR methodsNSNPbab→Beta, se→SEsePORMR Egger180.06650.0290.0381.069 (1.01–1.13)Weighted median180.05820.0290.0421.06 (1.00–1.12)Inverse variance weighted180.01740.0230.4591.02 (0.97–1.07)Simple mode180.01230.0610.8431.01 (0.90–1.14)Weighted mode180.05950.0270.0391.06 (1.01–1.12)a b→Beta, se→SEb Method→MR methods Open table in a new tab In conclusion, we supported the potential genetic association between Alzheimer's disease and COVID-19, which was mainly reflected in chr19:44,744,108–46,102,697 region. APOE, APOC1 and other related genes might be an important reason why patients with Alzheimer's disease were more susceptible to COVID-19. Although Alzheimer's disease might increase the risk of COVID-19, the causality was not clear enough (Table 1). We recommend that our views should be further validated in future clinical and observational studies. All the authors declare no conflicts of interest. This work was supported by the National Key Research and Development Program of China (2017YFC1201201, 2018YFC0910504 and 2017YFC0907503), the Natural Science Foundation of China (61801147 and 82003553) and Heilongjiang Postdoctoral Science Foundation (LBH-Z6064). We thank International Genomics of Alzheimer's Project (IGAP) and COVID-19 Host Genetics Initiative for providing GWAS summary statistics.