Abstract
Observational studies have suggested that SARS-CoV-2 infection increases the risk of neurological diseases, but it remains unclear whether the association is causal. The present study aims to evaluate the causal relationships between SARS-CoV-2 infections and neurological diseases and analyzes the potential routes of SARS-CoV-2 entry at the cellular level. We performed Mendelian randomization (MR) analysis with CAUSE method to investigate causal relationship of SARS-CoV-2 infections with neurological diseases. Then, we conducted single-cell RNA sequencing (scRNA-seq) analysis to obtain evidence of potential neuroinvasion routes by measuring SARS-CoV-2 receptor expression in specific cell subtypes. Fast gene set enrichment analysis (fGSEA) was further performed to assess the pathogenesis of related diseases. The results showed that the COVID-19 is causally associated with manic (delta_elpd, − 0.1300, Z-score: − 2.4; P = 0.0082) and epilepsy (delta_elpd: − 2.20, Z-score: − 1.80; P = 0.038). However, no significant effects were observed for COVID-19 on other traits. Moreover, there are 23 cell subtypes identified through the scRNA-seq transcriptomics data of epilepsy, and SARS-CoV-2 receptor TTYH2 was found to be specifically expressed in oligodendrocyte and astrocyte cell subtypes. Furthermore, fGSEA analysis showed that the cell subtypes with receptor-specific expression was related to methylation of lysine 27 on histone H3 (H3K27ME3), neuronal system, aging brain, neurogenesis, and neuron projection. In summary, this study shows causal links between SARS-CoV-2 infections and neurological disorders such as epilepsy and manic, supported by MR and scRNA-seq analysis. These results should be considered in further studies and public health measures on COVID-19 and neurological diseases.
Similar content being viewed by others
Avoid common mistakes on your manuscript.
Introduction
Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has emerged worldwide, resulting in 600 million infections and over 6 million deaths as of August 2022 according to the World Health Organization (WHO) report [1]. While it was initially thought to be restricted to the respiratory system, the adverse effects of COVID-19 on the central and peripheral nervous systems have been increasingly recognized [2].
Although the pathogenic mechanism and epidemiological features of SARS-CoV-2 are still largely unclear, some observational studies have reported findings suggesting that COVID-19 may be associated with an increased risk of neurological diseases. These neurologic disorders could be considered in three categories: (1) related to central nervous system, including headache [3, 4], confusion or impaired consciousness [5, 6], meningoencephalitis [7, 8], cerebrovascular disease [9, 10], and stroke [11, 12]; (2) related to peripheral nervous system, including taste and smell impairment [13, 14] and vision impairment [15, 16]; (3) muscular injury [17, 18]; and (4) related to altered mental status, including anxiety disorder [19] and psychotic disorder [20]. COVID-19 neuropathogenesis might involve the invasion of the nervous system by SARS-CoV-2 and cause neurological complications. Previous studies have shown that SARS-CoV-2 virus particles were found in the frontal lobes and cerebrospinal fluid (CSF) of patients with COVID-19 [21, 22]. Moreover, SARS-CoV-2 replication could be detected in the brains of human angiotensin-converting enzyme 2 (hACE2) knock-in mice and human neural tissue [23, 24]. Additionally, SARS-CoV-2 belongs to the same Betacoronavirus (β-CoV) genus as SARS-CoV, and they share approximately 76% amino acid identity [25,26,27]. Most β-CoVs exhibit a propensity for neuroinvasion [28]. However, the claims of neuroinvasion by SARS-CoV-2 in literatures have thus far been inconsistent [23, 29,30,31].
Furthermore, SARS-CoV-2 enters host cells using the receptor angiotensin-converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2) as same as SARS-CoV [32], but they alone cannot explain the significant differences in the primary infection sites and clinical manifestations exhibited by SARS-CoV-2 and SARS-CoV, suggesting the involvement of other receptors in SARS-CoV-2 host interactions [33, 34]. Therefore, a comprehensive investigation of the relationship between SARS-CoV-2 infection and neurological diseases, along with an exploration of the receptors that have played a role in the virally infected brain, is needed.
Mendelian randomization (MR) is an analytic approach that uses genetic variation as the proxy to examine the potential causal effect of an exposure (e.g., COVID-19) on the outcome (e.g., Neurological disorders). Different from observational studies, confounding bias can be minimized in MR studies because genetic variants are randomly allocated to the individual at birth. Similarly, reverse causation can be avoided because genetic variants are allocated before the development of the disease [35, 36]. In this study, we sought to evaluate the associations of COVID-19 with the risk of neurologic disorders using Causal Analysis Using Summary Effect estimates (CAUSE) analysis, a novel MR method that can avoid more false positives caused by correlated horizontal pleiotropy [37]. Moreover, single-cell RNA sequencing (scRNA-seq) analysis and fast gene set enrichment analysis (fGSEA) were employed to characterize and compare distinct cell subtypes between conditions and explore disease-related pathways [38].
Materials and Methods
Overview
MR is an increasingly popular approach that estimates the causal effect in observational epidemiological studies. Traditional MR methods rely on several strong, untestable assumptions, including (i) the genetic variant must be truly associated with the exposure; (ii) the genetic variant should not be associated with confounders of the exposure-outcome relationships; (iii) the genetic variant should only be related to the outcome of interest through the exposure under study. However, some of the strong assumptions required to make causal inferences in MR described previously are often violated, and thus, biases are introduced. It is thoughtful to take into account whether the interpretation of results violates the assumptions of this approach. Nevertheless, more robust methods have been proposed to overcome these limitations and enhance the discrimination of genetic associations with the outcome, distinguishing whether it is caused by a genetic causal relationship or by correlated and uncorrelated pleiotropic effects. Here, we performed a new MR method, CAUSE, which accounts for correlated and uncorrelated horizontal pleiotropic effects to assess the causal relationships of SARS-CoV-2 infections with neurological diseases. Then, we further conducted a single-cell transcriptome analysis to measure the expression and distribution of SARS-CoV-2 receptors and fGSEA, aiming to elucidate potential disease mechanism. The corresponding flow chart is presented in Fig. 1.
GWAS Summary Statistics for Exposure and Outcomes
We use CAUSE to test for causal effects of COVID-19 on 176 neurological disorders according to the 11th revision of International Classification of Diseases (ICD-11) [39]. The Genome-Wide Association Study (GWAS) summary statistics for exposure and outcomes are available in the IEU OpenGWAS database [40], and the detailed information is shown in Supplementary Table S1. We obtained the GWAS summary statistics according to the following selection criteria: (i) We identified neurological disorders within the chapters of Neurology in ICD-11, encompassing the following three chapters: “06 Mental, behavioral, or neurodevelopmental disorders,” “07 Sleep–wake disorders,” and “08 Diseases of the nervous system.” It is noteworthy that ICD-11 defines the concept of “multiple parenting,” allowing a disease to be classified in several chapters. For example, “Stroke” is list in several chapters: “8B20 Stroke not known if ischaemic or haemorrhagic,” “24 Factors influencing health status or contact with health services.” We still include it in our study. As long as the disease is in the neurological sections, it is included in the analysis; (ii) only the European participants were included. (iii) We prioritized studies with the largest possible sample sizes and the highest number of single-nucleotide polymorphisms (SNPs), and subsequently take into account the closest possible publication dates. Finally, a total of 173 GWAS datasets were selected for the MR analysis which include one COVID-19 study as the exposure group and 172 neurological disorder studies as the outcome groups.
IV Identification and MR Analysis
CAUSE computes joint density of all summary statistics for each variant, To account for this, this approach includes as much information from all variants as possible, including weakly associated variants (P < 10–3) and those with low mutual LD (r2 > 0.01), aiming to improve power [37]. Therefore, SNPs associated with COVID-19 at a slightly more lenient significance threshold (P < 5 × 10−6) were selected as potential instrumental variables (IVs). Then, based on the European-based 1000 Genomes projects reference panel, the linkage disequilibrium (LD) threshold for clumping was set to r2 > 0.01 within a 10,000 kb window using the “ld_clump” function of the R package “ieugwasr” (https://mrcieu.github.io/ieugwasr/). Finally, we estimated the nuisance parameters using the “est_cause_params” function of the R package “cause” (https://github.com/jean997/cause). Based on these nuisance parameters, the expected log pointwise posterior density (ELPD) was computed for sharing, causal, and null model, respectively.
ScRNA-seq Data Sources and SARS-CoV-2 Receptor Selection
To further validate the results of the MR analysis and explore the infection pathway of SARS-CoV-2 in these disorders, we selected neurological disorders with causal relationship with SARS-CoV-2 infection for scRNA-seq analysis. Among these identified disorders, only the scRNA-seq raw data for epilepsy are available, obtained from the Pfisterer U et al. [41]. Therefore, the subsequent analysis focuses only on the mechanisms of epilepsy. Furthermore, due to that the specific receptors for viruses are key to promote them entry into host cells and pathogenesis [32,33,34], we measured the expression of SARS-CoV-2 receptors in various cell subtypes and different disease states. The SARS-CoV-2 receptors were selected by searching all the possible studies in the databases of PubMed (http://www.ncbi.nlm.nih.gov/pubmed) and Google Scholar (http://scholar.google.com/) using the keywords: “SARS-CoV-2,” “COVID-19,” and “receptors”.
ScRNA-seq Analysis
The whole process of scRNA-seq data analysis was performed by R package Seurat [42]. Particularly, the low-quality cells with less than 500 detected genes or higher than 100,000 or mitochondrial gene expression exceeded 20% were excluded from the following analysis. SCTransform was used for normalization, variance stabilization, and feature selection. All data were scaled to weight for downstream analysis, and principal component analysis (PCA) and T-distributed Stochastic Neighbor Embedding (t-SNE) dimension reduction with top 40 principal components (PCs) were performed. A nearest-neighbor graph was calculated using FindNeighbors, followed by clustering identifying FindClusters with a resolution of 0.5. Marker genes of each cluster were identified by the FindAllMarkers with Wilcox t test, and annotation was performed based on databases including CellMarker and PanglaoDB [43, 44]. Finally, 106,527 cells were clustered. After cell type identification, feature plots were visualized to identify the expression of 20 receptors in each cluster.
Differential Abundance Test and Receptor Cellular Distribution
To further explain the causal association between SARS-CoV-2 infection and risk of epilepsy, we performed a differential abundance testing algorithm to identify disease-specific cell populations and explored the potential neuroinvasion routes by measuring SARS-CoV-2 receptor expression levels in each cell type. the differential abundance analysis was analyzed via the R package “Milo” by allocating cells to partially overlapping neighborhoods on a k-nearest neighbor (KNN) graph [42]. With calculated log2 fold change and FDR, clusters having statistically significant differential abundance were determined. We create a “Milo object” from a Seurat object that includes PCA and TSNE dimensionality reduction. Then, the “makeNhoods” function was employed to define representative neighborhoods, with the parameters “prop,” “k,” and “d” all set to their default values. The distribution of neighborhoods size is shown in Supplementary Figure S1. Conducting differential abundance analysis between conditions (normal vs epilepsy) in all neighborhoods, the procedure applied a weighted false discovery rate (FDR) to correct for multiple hypotheses. Subsequently, we measured the cellular distribution of SARS-CoV-2 receptors and compared the expression of each receptor among the cell subtypes using the “FeaturePlot” function of the R package “Seurat” [39].
Fast Gene Set Enrichment Analysis
To investigate and explore the biological signaling pathway, fGSEA was utilized respectively for oligodendrocyte and astrocyte cell subtypes in comparison with the remaining cell subtypes. The top 10 terms from C2 curated gene set and C5 ontology gene sets were presented. Significantly enriched pathways were illustrated based on NES (Net enrichment score) and P value. Gene sets with |NES|> 1and FDR q < 0.05 were deemed to be significantly enriched.
Results
Identification of Cell Subtypes
We conducted the scRNA-seq transcriptomics analysis on temporal cortex of 19 samples (including nine epilepsy patients and 10 controls without any neurological disorders) provided by Pfisterer U et al. [41]. After quality control and data normalization, a total of 29,212 RNA features and 106,527 cells were retained for downstream analysis. T-SNE was used for dimensional reduction for high-quality cells, and 23 different clusters were obtained eventually (Fig. 2).
Causal Effects of COVID-19 on Manic
For the manic trait, genetic predisposition to COVID-19 is associated with the risk of it. As Table 1 shows, when compared with the sharing model, the estimated difference in expected log pointwise posterior density (delta EPLD) in the causal models is negative, and significant differences are presented (delta EPLD = − 0.1300). Furthermore, the fitted delta EPLD of the causal model is still significantly better than the sharing model (z-score = − 2.4 and p value = 0.0082). This revealed different posterior distributions and proportions of correlated pleiotropic SNPs in the two models.
Causal Effects of COVID-19 on Epilepsy
For the epilepsy trait, there is a causal association between COVID-19 and it, suggesting that COVID-19 infection may increase the risk of epilepsy. As Table 2 shows, the fit of both the shared and causal models was significantly different from the null model (no causal or shared effects). The causal model trends to have a better fit than the sharing model and is statistically better than it.
Cell Subtypes Associated with Epilepsy
Next, we utilized Milo to calculate cell-neighbourhoods and performed differential cell abundance testing between control and epilepsy confirming that the abundance of cellular states was substantially different in all clusters (Fig. 3; spatial false discovery rate (FDR) < 0.05). The plot shows comparisons along the control and epilepsy, with neighborhoods that are significantly differentially abundant epilepsy samples shown in purple and neighborhoods that are significantly differentially abundant control samples shown in yellow. We identified that pyramidal, oligodendrocyte, mixed, Ex8, interneuron, and dopaminergic are significantly enriched both in epilepsy and healthy subjects and continuously distributed between them. This suggests that these cell subtypes are present throughout the duration of epilepsy. Then, fGSEA was performed to identify the functional enrichment of cell subtypes with receptor-specific expression (Supplementary Figure S2 to S5). Enrichment term exhibited that was mainly astrocyte cell subtypes associated with H3K27ME3, neuronal system, aging brain, neurogenesis, neuron projection, and other neurological enrichment. However, there was no significant neurological enrichment in selected terms for oligodendrocyte cell subtypes.
SARS-CoV-2 Receptor Expression
The cell-specific expression and distribution of the receptors determine the tropism of virus infection, which has a major implication for understanding its pathogenesis and designing therapeutic strategies. Our results showed that TTYH2 is specifically highly expressed in oligodendrocyte and astrocyte cell subtypes. The ACE2 and TMPRSS2 expressing cell ratio is relatively low, which is consistent with previous studies [45]. Expression of the other five receptors is also low. In addition, the expressions of ERGIC3, ASGR1, FUT8, KREMEN1, and LMAN2 are relatively high and not specifically expressed in any cluster. The expressions of receptors in each cluster are demonstrated in Figs. 4, 5, 6, and 7. Considering that oligodendrocyte and astrocyte cells have also been confirmed to play a key role in epilepsy pathogenesis [46, 47], the causal link between SARS-Cov-2 infection and epilepsy may be associated with these two cell subtypes.
Discussion
In this study, we performed MR analyses that found genetic liability to COVID‐19 to be associated with increased risk of epilepsy or manic among the 176 neurological disorder outcomes tested, which is consistent with multiple epidemiological studies reporting an association between neurological disorders and COVID-19 disease. We also performed the scRNA-seq analyses and fGSEA to further explain potential infection mechanisms.
Previous clinical studies have suggested that COVID-19 may trigger clinical manifestations of neurological disorders, notably manic and epilepsy. These complications have been frequently reported in association with COVID-19 [48, 49]. Approximately 13 of 1744 patients with COVID-19 (0.7%) have been reported to have steroid-induced mania and psychosis [50]. Another study firstly reported that specific IgG antibody for SARS-CoV-2 is detected from a specimen of CSF in a COVID-19 patient with manic-like symptoms [51]. Similarly, SARS-CoV-2 was detected in the serum and CSF of SARS patients with persistent epilepsy [52]. The MR results consistently indicated an elevated risk of genetic predisposition to manic and epilepsy in connection with COVID-19, aligning with epidemiological observations. In the single-cell analysis of epilepsy, the expression of receptors related to COVID-19 can be categorized into three scenarios: receptors with low expression level, such as ACE and CLEC4M; receptors exhibiting high expression across all cell clusters, such as FUT8 and KREMEN1; and the last category comprises receptors with specific high expression, exemplified by TTYH. Tweety homologs (TTYHs) include three members (TTYH 1–3) in humans that have been implicated in the pathogenesis of epilepsy. TTYH2 not only acts as a receptor for the SARS-CoV-2 but also as a calcium-activated chloride channel (CaCCs). Voltage-gated chloride channels (ClC) participate in the epileptogenesis process of epilepsy, and the inhibition of ClC may have anti-epileptic effect [53, 54]. Thus, the unbalanced expression levels of TTYH2 were one of the reasons for concomitant epilepsy in patients with COVID-19. The associations between COVID-19 and epilepsy and manic emphasize incorporating early intervention protocols into the care of COVID-19 patients which could contribute to better outcomes and improved quality of life.
Furthermore, mechanisms that increase the risk of neurological disorders in patients with COVID‐19 are complex. The fGSEA is a powerful method that focuses on gene sets to identify shared common biological functions or regulations. Epilepsy is a disease of aging; the incidence of epilepsy is highest in people over 65 [55]. H3K27me3 is a highly conserved repressive histone modification found in many central nervous system diseases and implicated in various neuronal processes [56, 57]. Previously, studies indicate that H3K27me3 levels increase with age in neurons, and high levels of H3K27me3 are potentially important in preserving adult neural function [58,59,60]. This suggests the potential relevance of this modification in various neuronal processes. Our findings also support the hypothesis that SARS-CoV-2 can enter the nervous system, thereby triggering the onset and progression of neurological diseases.
Apart from manic and epilepsy, no associations were found with COVID-19 exposures. The possible explanation is that if COVID-19 has a causal role in any of the outcomes’ susceptibility or severity, their effects may have been too small to be detected with our current sample sizes. It is noteworthy that relevant risk factors can still have clinical utility in identifying patients at risk, even if causality is disproved.
This study employed the CAUSE and single-cell transcriptome analysis to comprehensively assess the association between COVID-19 infection and prevalent neurological diseases. Additionally, fGSEA was conducted to evaluate the pathways implicated in the pathogenesis of epilepsy. However, our study also has limitations. Firstly, there are several modeling assumptions to be made when using MR, specifically that the genetic variants do not affect the considered outcomes through pathways independent of the exposure. Although this can never be completely ruled out, well-powered randomized trials are needed to conclusively assess this association. Secondly, due to the lack of scRNA-Seq data from patients infected with COVID-19 and causing neurological disease, we were unable to analyze receptor expression therein. Thirdly, both GWAS and scRNA-Seq data used in this study were predominantly obtained from European population ancestry; thus, these findings should be interpreted with caution when generalizing to other populations.
Conclusions
The present MR study unveiled an association between COVID-19 and epilepsy or manic symptoms. Through the analysis of scRNA-seq data, we observed elevated expression of SARS-CoV-2 receptors, particularly TTYH2, in seizure-related cell subtypes. Understanding the interaction of SARS-CoV-2 with these receptors could open avenues for early intervention and treatment, specifically targeting certain brain cell types in neurological diseases. A better understanding of SARS-CoV-2 infection and its interaction with neurological receptors can lead to the exploration of earlier interventions and treatments, focusing on specific brain cell types for the treatment of neurological diseases. The fGSEA results suggest that H3K27me3 may influence the onset of epilepsy, providing a new pathway for researchers to investigate the biological mechanisms of seizures and delve into new therapeutic targets. Overall, our study indicated the potential associations among SARS-Cov-2 infection and epilepsy or manic at genetic and transcriptomic level. Future research is necessary to investigate the underlying mechanisms linking COVID-19 with epilepsy, manic or other neurological diseases.
Data Availability
All the data used in this study can be acquired from the original genome-wide association studies and scRNA-seq that are mentioned in the text. Any other data generated in the analysis process can be requested from the corresponding author.
References
World Health Organization. [https://covid19.who.int/?gclid=EAIaIQobChMIn9OzgK7E6gIVyyMrCh0EnAwDEAAYASAAEgJgBvD_BwE]. Accessed Aug 2022
Chen YM, Zheng Y, Yu Y, Wang Y, Huang Q, Qian F, Sun L, Song ZG et al (2020) Blood molecular markers associated with COVID-19 immunopathology and multi-organ damage. EMBO J 39(24c):e105896
Xu XW, Wu XX, Jiang XG, Xu KJ, Ying LJ, Ma CL, Li SB, Wang HY et al (2020) Clinical findings in a group of patients infected with the 2019 novel coronavirus (SARS-Cov-2) outside of Wuhan, China: retrospective case series. BMJ 368:m606
Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, Zhang L, Fan G et al (2020) Clinical features of patients infected with 2019 novel coronavirus in Wuhan China. Lancet 395(10223c):497–506
Guedj E, Campion JY, Dudouet P, Kaphan E, Bregeon F, Tissot-Dupont H, Guis S, Barthelemy F et al (2021) (18)F-FDG brain PET hypometabolism in patients with long COVID. Eur J Nucl Med Mol Imaging 48(9c):2823–2833
Chen N, Zhou M, Dong X, Qu J, Gong F, Han Y, Qiu Y, Wang J et al (2020) Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet 395(10223c):507–513
Helms J, Kremer S, Merdji H, Clere-Jehl R, Schenck M, Kummerlen C, Collange O, Boulay C et al (2020) Neurologic features in severe SARS-CoV-2 infection. N Engl J Med 382(23c):2268–2270
Pilotto A, Masciocchi S, Volonghi I, De Giuli V, Caprioli F, Mariotto S, Ferrari S, Bozzetti S et al (2021) Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) encephalitis is a cytokine release syndrome: evidences from cerebrospinal fluid analyses. Clin Infect Dis 73(9c):e3019–e3026
Mao L, Jin H, Wang M, Hu Y, Chen S, He Q, Chang J, Hong C et al (2020) Neurologic manifestations of hospitalized patients with coronavirus disease 2019 in Wuhan China. JAMA Neurol 77(6c):683–690
Li Y, Li M, Wang M, Zhou Y, Chang J, Xian Y, Wang D, Mao L et al (2020) Acute cerebrovascular disease following COVID-19: a single center, retrospective, observational study. Stroke Vasc Neurol 5(3c):279–284
Paterson RW, Brown RL, Benjamin L, Nortley R, Wiethoff S, Bharucha T, Jayaseelan DL, Kumar G et al (2020) The emerging spectrum of COVID-19 neurology: clinical, radiological and laboratory findings. Brain 143(10c):3104–3120
Markus HS, Brainin M (2020) COVID-19 and stroke-a global World Stroke Organization perspective. Int J Stroke 15(4c):361–364
Giacomelli A, Pezzati L, Conti F, Bernacchia D, Siano M, Oreni L, Rusconi S, Gervasoni C et al (2020) Self-reported olfactory and taste disorders in patients with severe acute respiratory coronavirus 2 infection: a cross-sectional study. Clin Infect Dis 71(15c):889–890
Brann DH, Tsukahara T, Weinreb C, Lipovsek M, Van den Berge K, Gong B, Chance R, Macaulay IC et al (2020) Non-neuronal expression of SARS-CoV-2 entry genes in the olfactory system suggests mechanisms underlying COVID-19-associated anosmia. 6(31):eabc5801
Pereira LA, Soares LCM, Nascimento PA, Cirillo LRN, Sakuma HT, Veiga GLD, Fonseca FLA, Lima VL et al (2022) Retinal findings in hospitalised patients with severe COVID-19. Br J Ophthalmol 106(1c):102–105
Wu P, Duan F, Luo C, Liu Q, Qu X, Liang L, Wu K (2020) Characteristics of ocular findings of patients with coronavirus disease 2019 (COVID-19) in Hubei Province China. JAMA Ophthalmol 138(5c):575–578
Spinato G, Fabbris C, Polesel J, Cazzador D, Borsetto D, Hopkins C, Boscolo-Rizzo P (2020) Alterations in smell or taste in mildly symptomatic outpatients with SARS-CoV-2 infection. JAMA 323(20c):2089–2090
Soares MN, Eggelbusch M, Naddaf E, Gerrits KHL, van der Schaaf M, van den Borst B, Wiersinga WJ, van Vugt M et al (2022) Skeletal muscle alterations in patients with acute Covid-19 and post-acute sequelae of Covid-19. J Cachexia Sarcopenia Muscle 13(1c):11–22
Nicolini H (2020) Depression and anxiety during COVID-19 pandemic. Cir Cir 88(5c):542–547
Taquet M, Geddes JR, Husain M, Luciano S, Harrison PJ (2021) 6-month neurological and psychiatric outcomes in 236 379 survivors of COVID-19: a retrospective cohort study using electronic health records. Lancet Psychiat 8(5c):416–427
Neumann B, Schmidbauer ML, Dimitriadis K, Otto S, Knier B, Niesen WD, Hosp JA, Gunther A et al (2020) Cerebrospinal fluid findings in COVID-19 patients with neurological symptoms. J Neurol Sci 418:117090
Moriguchi T, Harii N, Goto J, Harada D, Sugawara H, Takamino J, Ueno M, Sakata H et al (2020) A first case of meningitis/encephalitis associated with SARS-coronavirus-2. Int J Infect Dis 94:55–58
Sun SH, Chen Q, Gu HJ, Yang G, Wang YX, Huang XY, Liu SS, Zhang NN et al (2020) A mouse model of SARS-CoV-2 infection and pathogenesis. Cell Host Microbe 28(1c):124–133 (e124)
Brann DH, Tsukahara T, Weinreb C, Lipovsek M, Van den Berge K, Gong B, Chance R, Macaulay IC et al (2020) Non-neuronal expression of SARS-CoV-2 entry genes in the olfactory system suggests mechanisms underlying COVID-19-associated anosmia. 6(31):eabc5801
Coronaviridae Study Group of the International Committee on Taxonomy of V (2020) The species Severe acute respiratory syndrome-related coronavirus: classifying 2019-nCoV and naming it SARS-CoV-2. Nat Microbiol 5(4c):536–544
Hoffmann M, Kleine-Weber H, Schroeder S, Kruger N, Herrler T, Erichsen S, Schiergens TS, Herrler G et al (2020) SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell 181(2c):271–280 (e278)
Zhou P, Yang XL, Wang XG, Hu B, Zhang L, Zhang W, Si HR, Zhu Y et al (2020) A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature 579(7798c):270–273
Glass WG, Subbarao K, Murphy B, Murphy PM (2004) Mechanisms of host defense following severe acute respiratory syndrome-coronavirus (SARS-CoV) pulmonary infection of mice. J Immunol 173(6c):4030–4039
Marshall M (2021) COVID and the brain: researchers zero in on how damage occurs. Nature 595(7868c):484–485
Cantuti-Castelvetri L, Ojha R, Pedro LD, Djannatian M, Franz J, Kuivanen S, van der Meer F, Kallio K et al (2020) Neuropilin-1 facilitates SARS-CoV-2 cell entry and infectivity. Science 370(6518c):856–860
Matschke J, Lutgehetmann M, Hagel C, Sperhake JP, Schroder AS, Edler C, Mushumba H, Fitzek A et al (2020) Neuropathology of patients with COVID-19 in Germany: a post-mortem case series. Lancet Neurol 19(11c):919–929
Lukassen S, Chua RL, Trefzer T, Kahn NC, Schneider MA, Muley T, Winter H, Meister M et al (2020) SARS-CoV-2 receptor ACE2 and TMPRSS2 are primarily expressed in bronchial transient secretory cells. EMBO J 39(10c):e105114
Gu Y, Cao J, Zhang X, Gao H, Wang Y, Wang J, He J, Jiang X et al (2022) Receptome profiling identifies KREMEN1 and ASGR1 as alternative functional receptors of SARS-CoV-2. Cell Res 32(1c):24–37
Wang S, Qiu Z, Hou Y, Deng X, Xu W, Zheng T, Wu P, Xie S et al (2021) AXL is a candidate receptor for SARS-CoV-2 that promotes infection of pulmonary and bronchial epithelial cells. Cell Res 31(2c):126–140
Davies NM, Holmes MV, Davey Smith G (2018) Reading Mendelian randomisation studies: a guide, glossary, and checklist for clinicians. BMJ 362:k601
Huang L, Wang Y, Tang Y, He Y, Han Z (2022) Lack of causal relationships between chronic hepatitis C virus infection and Alzheimer’s disease. Front Genet 13:828827
Morrison J, Knoblauch N, Marcus JH, Stephens M, He X (2020) Mendelian randomization accounting for correlated and uncorrelated pleiotropic effects using genome-wide summary statistics. Nat Genet 52(7c):740–747
Korotkevich G, Sukhov V, Budin N, Shpak B, Artyomov MN, Sergushichev A (2016) Fast gene set enrichment analysis. bioRxiv. https://doi.org/10.1101/060012
Harrison JE, Weber S, Jakob R, Chute CG (2021) ICD-11: an international classification of diseases for the twenty-first century. BMC Med Inform Decis Mak 21(Suppl 6c):206
Lyon MS, Andrews SJ, Elsworth B, Gaunt TR, Hemani G, Marcora E (2021) The variant call format provides efficient and robust storage of GWAS summary statistics. Genome Biol 22(1c):32
Pfisterer U, Petukhov V, Demharter S, Meichsner J, Thompson JJ, Batiuk MY, Asenjo-Martinez A, Vasistha NA et al (2020) Identification of epilepsy-associated neuronal subtypes and gene expression underlying epileptogenesis. Nat Commun 11(1c):5038
Hao Y, Hao S, Andersen-Nissen E, Mauck WM 3rd, Zheng S, Butler A, Lee MJ, Wilk AJ et al (2021) Integrated analysis of multimodal single-cell data. Cell 184(13c):3573–3587 (e3529)
Zhang X, Lan Y, Xu J, Quan F, Zhao E, Deng C, Luo T, Xu L et al (2019) Cell Marker: a manually curated resource of cell markers in human and mouse. Nucleic Acids Res 47(D1c):D721–D728
Franzen O, Gan LM, Bjorkegren JLM (2019) PanglaoDB: a web server for exploration of mouse and human single-cell RNA sequencing data. Database (Oxford) 2019:baz046
Fagerberg L, Hallstrom BM, Oksvold P, Kampf C, Djureinovic D, Odeberg J, Habuka M, Tahmasebpoor S et al (2014) Analysis of the human tissue-specific expression by genome-wide integration of transcriptomics and antibody-based proteomics. Mol Cell Proteomics 13(2c):397–406
Jiang M, Lee CL, Smith KL, Swann JW (1998) Spine loss and other persistent alterations of hippocampal pyramidal cell dendrites in a model of early-onset epilepsy. J Neurosci 18(20c):8356–8368
Stefanits H, Czech T, Pataraia E, Baumgartner C, Derhaschnig N, Slana A, Kovacs GG (2012) Prominent oligodendroglial response in surgical specimens of patients with temporal lobe epilepsy. Clin Neuropathol 31(6c):409–417
Russo M, Calisi D, De Rosa MA, Evangelista G, Consoli S, Dono F, Santilli M, Gambi F et al (2022) COVID-19 and first manic episodes: a systematic review. Psychiatry Res 314:114677
Smith CM, Gilbert EB, Riordan PA, Helmke N, von Isenburg M, Kincaid BR, Shirey KG (2021) COVID-19-associated psychosis: a systematic review of case reports. Gen Hosp Psychiat 73:84–100
Rogers JP, Chesney E, Oliver D, Pollak TA, McGuire P, Fusar-Poli P, Zandi MS, Lewis G et al (2020) Psychiatric and neuropsychiatric presentations associated with severe coronavirus infections: a systematic review and meta-analysis with comparison to the COVID-19 pandemic. Lancet Psychiat 7(7c):611–627
Lu S, Wei N, Jiang J, Wu L, Sheng J, Zhou J, Fang Q, Chen Y et al (2020) First report of manic-like symptoms in a COVID-19 patient with no previous history of a psychiatric disorder. J Affect Disord 277:337–340
Jarrahi A, Ahluwalia M, Khodadadi H, de Silva Lopes Salles E, Kolhe R, Hess DC, Vale F, Kumar M et al (2020) Neurological consequences of COVID-19: what have we learned and where do we go from here? J Neuroinflammation 17(1c):286
Li B, Hoel CM, Brohawn SG (2021) Structures of tweety homolog proteins TTYH2 and TTYH3 reveal a Ca(2+)-dependent switch from intra- to intermembrane dimerization. Nat Commun 12(1c):6913
Shen KF, Yang XL, Liu GL, Zhu G, Wang ZK, Shi XJ, Wang TT, Wu ZF et al (2021) The role of voltage-gated chloride channels in the epileptogenesis of temporal lobe epilepsy. EBioMedicine 70:103537
Sen A, Capelli V, Husain M (2018) Cognition and dementia in older patients with epilepsy. Brain 141(6c):1592–1608
Liu PP, Xu YJ, Teng ZQ, Liu CM (2018) Polycomb repressive complex 2: emerging roles in the central nervous system. Neuroscientist 24(3c):208–220
Ritchie FD, Lizarraga SB (2023) The role of histone methyltransferases in neurocognitive disorders associated with brain size abnormalities. Front Neurosci 17:989109
Ma Z, Wang H, Cai Y, Wang H, Niu K, Wu X, Ma H, Yang Y et al (2018) Epigenetic drift of H3K27me3 in aging links glycolysis to healthy longevity in Drosophila. Elife 7:e35368
Ye L, Fan Z, Yu B, Chang J, Al Hezaimi K, Zhou X, Park NH, Wang CY (2012) Histone demethylases KDM4B and KDM6B promotes osteogenic differentiation of human MSCs. Cell Stem Cell 11(1c):50–61
Osako T, Lee H, Turashvili G, Chiu D, McKinney S, Joosten SEP, Wilkinson D, Nielsen TO et al (2020) Age-correlated protein and transcript expression in breast cancer and normal breast tissues is dominated by host endocrine effects. Nat Cancer 1(5c):518–532
Acknowledgements
We thank the GWAS summary statistics provided by MR-Base platform. We are grateful that the scRNA-seq data for epilepsy studies are publicly available. We also thank the technical support of the Supercomputer Center of Chongqing Medical University for the numerical calculation of this study, and we thank all the investigators and participants who contributed to those studies.
Funding
This research is financially supported by the Science and Technology Research Program of Chongqing Municipal Education Commission (Grant No. KJQN202100402), National Natural Science Foundation of China (Grant No. 32200446), and CQMU Program for Youth Innovation in Future Medicine, Chongqing Medical University (Grant No. W0147).
Author information
Authors and Affiliations
Contributions
ZH designed the research. LH, YW, YH, DH, TW, and ZH collected the data. LH and ZH performed the research and analyzed the data. LH wrote the paper. ZH reviewed and modified the article. All authors discussed the results and contributed to the final article. All authors read and approved the final article.
Corresponding author
Ethics declarations
Ethics Approval
Not applicable.
Consent for Participate
Not applicable.
Consent for Publication
All authors read and approved the final manuscript.
Conflict of Interests
The authors declare no competing interests.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary Information
Below is the link to the electronic supplementary material.
Rights and permissions
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
About this article
Cite this article
Huang, L., Wang, Y., He, Y. et al. Association Between COVID-19 and Neurological Diseases: Evidence from Large-Scale Mendelian Randomization Analysis and Single-Cell RNA Sequencing Analysis. Mol Neurobiol (2024). https://doi.org/10.1007/s12035-024-03975-2
Received:
Accepted:
Published:
DOI: https://doi.org/10.1007/s12035-024-03975-2