Genetic analyses point to alterations in immune-related pathways underpinning the association between psychiatric disorders and COVID-19

doi:10.21203/rs.3.rs-3791588/v1

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Genetic analyses point to alterations in immune-related pathways underpinning the association between psychiatric disorders and COVID-19

https://doi.org/10.21203/rs.3.rs-3791588/v1

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Current literature suggests that people with psychiatric disorders have higher risk of SARS-CoV-2 infection and a worse prognosis of the disease. We aimed to study the genetic contribution to these associations in a range of psychiatric disorders and COVID-19, and determine whether these are unique or shared across psychiatric disorders. Using the largest available genome-wide association studies, we analysed the genetic overlap between six psychiatric disorders and COVID-19. We further identified specific regions of the genome that are shared across the psychiatric disorders and COVID-19 using pairwise GWAS, and examined which genes are present in these regions. Finally, we sought evidence for causal associations using Mendelian Randomization methods. We found a significant genetic overlap between depression and ADHD, with both COVID-19 susceptibility and severity, as well as between anxiety and COVID-19 severity. We identified specific regions of the genome shared between several psychiatric disorders and COVID-19. However, no region was common across all psychiatric disorders and COVID-19. Gene-based analysis in these genomic regions suggested possible links with immune-related pathways such as thyroid homeostasis, inflammation and stress response. Finally, we provide evidence of a potential causal relationship between ADHD and higher COVID-19 susceptibility and severity, and between depression and higher susceptibility to COVID-19. Our results support the hypothesis that the relationship between psychiatric disorders and COVID-19 risk is likely due to shared alterations in immune-related pathways and are not as a result of environmental factors alone, shedding light on potentially viable therapeutic targets.

Biological sciences/Genetics

Health sciences/Diseases/Psychiatric disorders

The COVID-19 pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has led to an unprecedented global health problem due to the high contagion and mortality rates of the virus. (1) Nevertheless, not everyone is equally affected by the disease. One population particularly vulnerable to the effects of COVID-19 disease is people with pre-existing psychiatric disorders. A recent umbrella review showed that this subgroup is more susceptible to SARS-CoV-2 infection, more likely to develop a severe form of the disease, and has a higher risk of COVID-19-related mortality. (2) However, the association between psychiatric disorders and COVID-19 outcomes is variable. For instance, while evidence supports an increased risk of COVID-19 hospitalization and mortality in people with schizophrenia, mood disorders and autism spectrum disorders (ASD), (2, 3) this is not observed in people with anxiety, (2) and results are mixed for people with attention deficit and hyperactivity disorder (ADHD). (4, 5) Likewise, higher infection rates have been reported in people with anxiety and ADHD, (2, 4) but results are not consistent for people with schizophrenia and mood disorders. (2) These observations indicate that there may be differences in both the susceptibility to COVID 19 and the severity of symptoms experienced in individuals with various psychiatric disorders.

Differences in transmissibility and pathogenicity of SARS-CoV-2 among people with psychiatric disorders might be explained by both psychosocial factors such as cognitive impairment, shared living facilities, psychotropic medication or health behaviours, and biological/genetic factors. (6, 7) Some studies have reported common alterations in biological pathways for psychiatric disorders and COVID-19, (8) which suggests a potential role for shared common genetic risk factors between both conditions. In line with these observations, a genetic predisposition to psychiatric disorders has been associated with COVID-19 susceptibility and severity, (9) and recent studies have reported significant genetic correlations between depression and COVID-19. (10) Despite shared genetic overlap, studies using genetic data have failed to find evidence of causal associations between selected psychiatric disorders and COVID-19 in support of the results obtained in observational studies. (11, 12) Additionally, more studies are needed focusing on other psychiatric disorders, such as anxiety or ASD, for which literature is scarce.

While there is some evidence pointing towards shared biological aetiology underpinning the vulnerability to certain psychiatric disorders and COVID-19 outcomes, little is known about which biological pathways or genes may contribute to these observations, or whether these mechanisms are unique or shared across psychiatric disorders. A recent study has identified a number of differentially expressed immune-related genes that are shared across psychiatric disorders such as mood disorders and schizophrenia, and COVID-19. (13) However, no study has yet compared the shared genomic overlap across a wide array of psychiatric disorders and COVID-19.

We aimed to extend current knowledge regarding the genetic links between six psychiatric disorders and COVID-19, and test for any causal associations. To do this we i) examined whether shared genetic factors may underpin differences in transmissibility and pathogenicity of SARS-CoV-2 observed among different psychiatric disorders, ii) identified which specific regions of the genome are shared between each disorder and COVID-19 and iii) tested for causal associations using Mendelian Randomization.

2.1 Data

2.1.1 Psychiatric disorders

We examined the relationship between six psychiatric disorders and two COVID-19 traits. We used the summary statistics from the latest genome-wide association studies (GWAS) available of depression (246 363 cases and 561 190 controls), (14) ADHD (38 691 cases and 186 843 controls), (15) ASD (18 381 cases and 27 969 controls), (16) bipolar disorder (41 917 cases and 371 549 controls), (17) schizophrenia (76 755 cases and 243 649 controls) (18) and anxiety (25 453 cases and 58 113 controls). (19) For further information regarding data acquisition and phenotype definitions for each cohort, see the corresponding reference. The inclusion of these psychiatric disorders was based on prior literature reporting associations with COVID-19 outcomes.

2.1.2 COVID-19

We obtained the summary statistics of SARS-CoV-2 infection (159 840 cases and 2 782 977 controls) and COVID-19 hospitalization (44 986 cases and 2 356 386 controls) from the release 7 of the COVID-19 Host Genetics Initiative GWAS meta-analyses, (20) excluding 23andMe Inc. data. Infection cases were defined as individuals with a laboratory confirmed SARS-CoV-2 infection (RNA and/or serology based), a diagnosis of COVID-19 made by a physician or self-reporting a positive COVID-19 test (e.g. through a questionnaire). Hospitalization cases were defined as individuals hospitalized due to COVID-19 related symptoms and with a laboratory confirmed SARS-CoV-2 infection. (21) From this point on, we will refer to SARS-CoV-2 infection as susceptibility and to COVID-19 hospitalization as severity.

2.2 Genetic correlations between psychiatric disorders and COVID-19 traits

We estimated genetic correlations between the six psychiatric disorders of interest and COVID-19 susceptibility and severity using Linkage Disequilibrium score regression (LDSC). (22) For all the disorders and COVID-19 phenotypes, we obtained their European-only summary statistics. Significance values were corrected for multiple testing bias using a Bonferroni correction (0.05/12 = 0.004).

2.3 Pairwise GWAS

We used the pairwise GWAS method (GWAS-PW) (23) to identify shared causal risk loci between each of the 6 psychiatric disorders and COVID-19 susceptibility and severity. This method splits the genome into 1703 independent regions and calculates, for each of these regions, the posterior probability of association (PPA) of four different models: (1) the region is unique to the psychiatric disorder, (2) it is unique to the COVID-19 trait, (3) it is shared by both traits through the same causal variants and (4) it is associated with both traits but through different variants. To do so, the GWAS-PW method needs the correlation between effect sizes in non-associated regions of the genome to avoid potential confounding due to sample overlap between traits. Thus, we used the command-line tool fGWAS, implemented in PW-GWAS, to calculate the PPA for each region separately, for both traits. In order to obtain a proxy estimate of sample overlap, regions with a PPA < 0.2 in both traits were selected and the correlation in SNP effect sizes between the two traits was determined and incorporated into the models. We selected those regions with the highest PPA for model 3 (with a cut-off of PPA > 0.5), as we were only interested on those regions shared between the psychiatric disorder and the COVID-19 trait through the same causal variants. An ideogram showing these shared regions was created using http://visualization.ritchielab.org/phenograms/plot.

2.4 Gene mapping of shared regions and drug-gene interactions

We uploaded to the FUMA platform v1.5.4(24) the summary statistics of the six psychiatric disorders and the two COVID-19 traits for putative functional annotation. Then, we used MAGMA v1.10, a tool for gene-based analysis and generalized gene-set analysis of GWAS data, to map protein-coding genes in the identified regions.(25) A Bonferroni correction was applied (0.05/total number of genes in shared regions). We uploaded the results to Cytoscape software v3.10.0 to create an association network.(26) Finally, the identified genes were uploaded to Drug Gene Interaction Database (DGIdb)(27) to check for potential interactions with drugs.

2.5 Causality tests

We used Mendelian randomization (MR) methods to determine whether any of the psychiatric disorders of interest were causally associated with COVID-19 susceptibility and severity, or if there was evidence of reverse causality. This method identifies causal associations between traits using SNPs that are robustly associated with your exposure trait as instrumental variables (IVs). To be IVs, these SNPs have to be associated with your exposure trait and only be associated with the outcome trait through the exposure. Moreover, these SNPs cannot be associated with a confounding variable (horizontal pleiotropy). The rational of the method is based on the natural randomization of SNPs happening during meiosis, when the population is divided into case and control groups for a given risk factor based on the genetics of each individual, akin to randomized control trials. Therefore, MR can infer causality because the direction of the effect is clear, going always from the IV to the risk factor. (28)

We used generalized summary-data-based Mendelian randomization (GSMR) for our primary analysis. (29) Using full GWAS summary statistics, GSMR clumps SNPs using a linkage disequilibrium reference panel derived from 50,000 individuals from the UK Biobank while adjusting for heterogeneous SNP-outliers using HEIDI-filtering to provide a single MR estimate, adjusted for pleiotropic effects between traits. (29) Moreover, we performed four different MR analyses (IVW, penalized weighted median, weighted median and weighted mode) as sensitivity analyses. We used Plink to select the IVs through clumping of genome-wide significant SNPs (--clump kb 1000 kb, --clump r2 < 0.001), (30) and then we performed the MR analyses using the ‘TwoSampleMR’ package from MR-Base. (31)

3.1 Genetic correlation analysis

Depression and ADHD were positively correlated with COVID-19 susceptibility (r_{g DEP} = 0.090, SE: 0.034, p = 0.007; r_{g ADHD} = 0.274, SE: 0.040, p = 4x10^− 12 ; Fig. 1); however, the genetic correlation with depression was no longer significant after Bonferroni multiple testing correction. Depression, ADHD and anxiety were also significantly positively correlated with COVID-19 severity (r_{g DEP} = 0.125, SE: 0.028, p = 5.6x10^− 6; r_{g ADHD} = 0.251, SE: 0.041, p = 1.2x10^− 9, r_{g ANX} = 0.145, SE: 0.041, p = 0.0004; Fig. 1). Bipolar disorder, schizophrenia and ASD were not significantly correlated with either COVID-19 susceptibility or severity.

3.2 Pairwise GWAS

We used PW-GWAS to identify the specific regions shared between the six psychiatric disorders and COVID-19 susceptibility and severity, regardless of whether a global genetic correlation had been found. Using a PPA cut-off of > 0.5, we identified five different regions of the genome that were causally shared between any of the examined psychiatric disorders and COVID-19 susceptibility, and six between any of the psychiatric disorders and COVID-19 severity (Supplementary Tables 1–12). Three of these regions were in chromosome 17 (chr17q12, chr17q21.3, chr17q24.1-q24.2), two in chromosome 4 (both in chr4q24), one in chromosome 19 (chr19q13.32-q13.33) and another in chromosome 1 (chr1p31.1) (Fig. 2, Supplementary table 13). Interestingly, despite global genetic correlations, we did not identify specific shared genomic regions between ADHD and anxiety, and either COVID-19 susceptibility or severity. On the contrary, despite non-significant global genetic correlations, we found specific shared genomic regions between schizophrenia, bipolar and ASD, and both COVID-19 traits. One region on chromosome 17 (chr17q12) was largely split between being associated with model 3 (PPA: 0.43) and model 4 (PPA: 0.57) for bipolar disorder.

3.3 Gene mapping of shared regions and drug-gene interactions

We mapped SNPs in the identified genomic regions that are shared through the same causal variants to protein-coding genes. Four of our six psychiatric disorders had significantly enriched genes for at least one of the shared genomic regions after Bonferroni correction for multiple testing. As no shared genomic regions were found between COVID-19 susceptibility and severity, and anxiety or ADHD, these phenotypes were not included in gene-based tests. In total, we identified 23 overlapping genes between any of the psychiatric disorders of interest and either COVID-19 susceptibility or severity, the majority of them mapping to chromosome 17 (Fig. 3, Supplementary table 13). Across the six psychiatric disorders, schizophrenia had the most shared genes with COVID-19 susceptibility and severity (6 and 13 genes, respectively). Bipolar disorder and depression, unlike schizophrenia and ASD, shared genes with COVID-19 susceptibility but not severity. Among the identified genes, MED24 and THRA were significant for both depression and bipolar disorder, while CRHR1, SPPL2C, MAPT, STH, NSF, PLEKHM1, ARL17B, ARHGAP27 and KANSL1 genes were shared between schizophrenia and ASD. None of the identified genes were significant across all four psychiatric disorders. Results from the gene-based tests for each psychiatric disorder and COVID-19 traits can be found in Supplementary tables 14–20.

Finally, we uploaded the identified genes in DGIdb to search for potential interactions with drugs. Among all 23 genes, CRHR1 was significant for ASD, schizophrenia, severity and susceptibility (Supplementary table 21). CRHR1 interacted with Verucerfont, Pexacerfont or Emicerfont, CRF1 antagonists that are under investigation as potential treatments for anxious alcoholism, or Fluoxetine, a known antidepressant. On the other hand, CRHR1 also interacted with drugs related to lung diseases such as Budesonide and Triamcinolone, corticosteroids used to treat asthma, and Telavancin, used to treat pneumonia. Furthermore, we found an interaction between THRA (significant for depression, bipolar disorder and COVID-19 susceptibility) and lithium, a mood stabilizer.

3.4 Mendelian Randomization

Using GSMR, we observed a potential causal relationship between genetic risk for ADHD and depression, and COVID-19 susceptibility [OR_ADHD = 1.03, 95%CI: 1.00-1.06, p = 0.041; OR_DEP = 1.05, 95%CI: 1.00-1.11, p = 0.048] (Fig. 4). However, although all MR methods showed an aligned effect of ADHD and depression on COVID-19 susceptibility, not all MR estimates reached statistical significance (Supplementary table 22). Furthermore, only ADHD was causally associated with increased COVID-19 severity risk [OR_ADHD = 1.11, 95%CI: 1.04–1.18, p = 0.001]. Again, although all MR methods agreed on a positive effect on COVID-19 severity, not all MR estimates reached statistical significance. Remarkably, a significant causal association was observed between bipolar disorder and lower COVID-19 severity [OR_BIP = 0.93; 95%CI: 0.88–0.98, p = 0.005]. However, sensitivity analyses did not corroborate this result (Supplementary table 22). Interestingly, bidirectional GSMR analyses, but not any of the other MR estimates, showed evidence of reverse causality between schizophrenia and COVID-19 susceptibility, indicating that genetic predisposition to COVID-19 susceptibility might influence risk of schizophrenia [OR_SCZ = 1.17, 95%CI: 1.04–1.33, p = 0.009], and not the other way around. Evidence of reverse causality was not found for any of the other psychiatric disorders (Supplementary table 22).

The aim of this study was to examine the genetic relationship between six psychiatric disorders (depression, bipolar disorder, schizophrenia, ASD, ADHD and anxiety) and COVID-19 susceptibility and severity using post-GWAS statistical methods. We found evidence of significant genetic correlations between ADHD, depression and COVID-19 susceptibility and severity, and between anxiety and severity after correcting for multiple testing. While prior studies have reported significant genetic correlations between depression and COVID-19 outcomes, (10) our study is the first to report significant positive correlations between ADHD, anxiety, and COVID-19. In contrast, we did not find significant genome-wide genetic association between bipolar disorder, schizophrenia and ASD and any COVID-19 outcome, which is in line with current literature. (32, 33)

To further investigate the shared genetic architecture between our psychiatric disorders of interest and COVID-19, we examined specific shared genomic regions. We found two regions that were shared between depression and COVID-19 susceptibility, while no region was shared with severity. Gene-based tests conducted on these regions revealed two genes in chromosome 17: MED24 and THRA. Alternatively, despite the lack of global genetic correlation between bipolar disorder and either COVID-19 susceptibility or severity, we found evidence of two shared genomic regions, one shared with susceptibility and the other with severity. While no significant genes were shared between bipolar disorder and COVID-19 severity, six genes were identified for COVID-19 susceptibility, among them MED24 and THRA – as was seen with depression. MED24, which codifies for a mediator complex, has been associated with white cells count. (34) However, the role of this gene in psychiatric disorders is still unclear. THRA is a thyroid hormone receptor (THR) gene. (35) THRs are involved in brain development and function, (36) and alterations in THRs, including THRA, have been reported in many psychiatric disorders. (37, 38) Interestingly, mutations in THRA have been associated to a reduced white blood cell count (34) and B cell deficiency in mice, (39) suggesting a role in the immune response. Additionally, THRA has been shown to play a crucial role in lung regeneration after infection. (40) Thus, alterations in THRA could increase the risk of mood disorders while also leading to a compromised immune system, what may underlie, at least in part, the reported increased susceptibility to COVID-19 infection reported in people with mood disorders in some epidemiological studies. (5)

This is further supported by our observed tendency towards a causal association between depression risk and increased COVID-19 susceptibility, but not severity, which is in line with current literature. (10, 12) Given that people with mood disorders have a higher risk of subclinical hypothyroidism, (41, 42) we could hypothesize that a reduced thyroid functioning, probably caused by THRA malfunction, could be increasing the susceptibility to COVID-19 in this population. However, a recent MR study suggested that COVID-19 susceptibility causes hypothyroidism and not the other way around. (43) Although the exact role of THRA in both mood disorders and COVID-19 susceptibility is unclear, evidence suggests that altered thyroid function may play a role in this association and warrants further investigation.

The lack of genetic correlation between schizophrenia, ASD and any COVID-19 suggested that genome-wide common genetic effects do not explain the association between these disorders and COVID-19. Nevertheless, we found evidence of 4 regions in chromosomes 4, 19 and 17 shared between schizophrenia and COVID-19. The region on chromosome 17 was also shared between ASD and COVID-19 susceptibility and severity. Gene-based analysis conducted on this region identified 9 genes that were significantly enriched in schizophrenia, ASD and COVID-19. These include CRHR1, the corticotropin releasing hormone receptor 1, which plays a role in the hypothalamic-pituitary-adrenal (HPA) axis activation and is crucial in the physiological response to stress. (44) Moreover, CRHR1 is important for the immune response as it exerts both indirect anti-inflammatory effects through the production of cortisol, which supress immune function, and direct proinflammatory effects on immune cells. (45)

Given its role in stress response, CRHR1 has been associated with several psychiatric disorders. For instance, increased methylation levels in CRHR1 have been linked to more negative effects on health care workers’ mental health during the COVID-19 pandemic. (46) Alterations in CRHR1 have also been linked to higher levels of proinflammatory cytokines in people with schizophrenia. (47) Results from animal studies showed that blockage of CRHR1 receptor in mice infected with streptococcus pneumonia increased neutrophil infiltration in lungs but did not confer resistance to the infection, (48) and mutations in CRHR1 have been associated with neutrophil and lymphocyte count. (49) Neutrophils are important in the fight against pulmonary infections, but dysregulations in neutrophil’s function are linked to uncontrolled inflammatory reactions that can result in lung damage and sepsis. (50) It is well known that pneumonia is the most common cause of COVID-19-related hospitalization. (51) Thus, it is possible that in people with psychiatric disorders, and specifically schizophrenia and ASD, alterations in CRHR1 are contributing to the increased severity and mortality reported in observational studies (2) through the dysregulation of neutrophil’s function. In order to validate these biological pathways, we sought for drug-gene interactions with the CRHR1 gene. We identified interactions with CRF1 antagonists such as Verucerfont, Pexacerfont or Emicerfont, which are under investigation as potential treatments for stress-induced alcoholism, (52, 53) and also with the antidepressant Fluoxetine. Interestingly, Fluoxetine has been reported to exert antiviral and anti-inflammatory activities against SARS-CoV-2 infection. (54, 55) Furthermore, CRHR1 also interacted to Budesonide and Triamcinolone, corticosteroids used to treat asthma, and Telavancin, an antibiotic used to treat pneumonia.

Surprisingly, despite global genetic correlations, we did not find any genomic region shared between ADHD or anxiety and any COVID-19. The polygenic architecture of these traits might explain the lack of shared genomic regions; while we could observe a strong association at a global level, caused by multiple genes with tiny individual effects, it might be challenging to identify specific genomic regions with substantial effects shared between our traits. Another reason might be the lack of statistical power to detect causal variants in the anxiety and ADHD GWAS, which is key to identify shared genomic regions with confidence. (56) Nevertheless, we observed a potential causal association between ADHD and increased susceptibility and severity of COVID-19, which confirm prior results obtained in smaller samples. (12) Demontis et al., found that almost all variants influencing ADHD also influenced smoking, 79% of which had concordant directions. (15) Given that smoking is a known risk factor for severe COVID-19, (57) it is plausible that the causal association between ADHD and increased severity of COVID-19 is driven by smoking habits rather than by shared genetic causes.

Finally, we should highlight that all significant genes shared between more than one psychiatric disorder and COVID-19 were located on chromosome 17, specifically in 17q12-q21, a region that has been linked to immune response. (58, 59) In addition, the potential causal genes identified in this study converge on the endocrine axis HPA and hypothalamic-pituitary-thyroid (HPT), two connected biological pathways that play an important role in stress and immune response. (60) Therefore, while different genes have been identified across different psychiatric disorders in relation to COVID-19 susceptibility and severity, our results suggest that immune responses may be behind the increased vulnerability of people with psychiatric disorders to COVID-19. These results, if confirmed, might open the way for new targets for suitable therapeutic approaches.

The main strength of our study is the use of datasets from the largest available GWAS of various psychiatric disorders and COVID-19 traits. Moreover, to the best of our knowledge, it is the first study to explore shared causal risk loci between six different psychiatric disorders and COVID-19 traits using consistent methodology. However, this study should be considered in the light of several limitations. First, all GWAS results used in this study were obtained from cohorts of European ancestry, so our results might not represent other ancestry groups. Second, the power of the original GWAS is key for most of the analysis performed in our study. Thus, a non-significant result does not necessary reflect a true lack of association. Third, MR needs a strict list of assumptions to be met, which is challenging when analysing polygenic traits. Even though we have endeavoured to exclude pleiotropic SNPs, we cannot certify that this assumption has not been violated. Fourth, our study does not account for complex gene-gene interactions that may play a significant role in the observed relationships between psychiatric disorders and COVID-19. Finally, we are missing the role of potential cofounding variables such as BMI or vaccination on COVID-19 susceptibility and severity, which could not be taken into account due to the study design.

In conclusion, our results support that the relationship between psychiatric disorders and COVID-19 risk is likely due to shared alterations in immune-related pathways such as thyroid and inflammatory dysfunction, and impaired stress response, and is not as a result of environmental factors alone. Exploring new targets and drug repositioning strategies for medications traditionally employed in the treatment of stress-related and thyroid disorders holds promising potential to enhance COVID-19 and similar viral infection outcomes among individuals with psychiatric disorders.

DISCLOSURES

The authors declare no competing interests.

Supplementary information is available at MP’s website

ACKNOWLEDGEMENTS

This work was supported by the European Union's Horizon 2020 Framework Program under grant agreement No 101016127 (AM-M). We would like to thank the research participants and employees of the Psychiatric Genomics Consortium (PGC) and the COVID-19 Host genomics consortium for making this work possible.

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The authors have declared there is NO conflict of interest to disclose

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You are reading this latest preprint version

Genetic analyses point to alterations in immune-related pathways underpinning the association between psychiatric disorders and COVID-19

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Abstract

Figures

1. INTRODUCTION

2. METHODS

2.1 Data

2.1.1 Psychiatric disorders

2.1.2 COVID-19

2.2 Genetic correlations between psychiatric disorders and COVID-19 traits

2.3 Pairwise GWAS

2.4 Gene mapping of shared regions and drug-gene interactions

2.5 Causality tests

3. RESULTS

3.1 Genetic correlation analysis

3.2 Pairwise GWAS

3.3 Gene mapping of shared regions and drug-gene interactions

3.4 Mendelian Randomization

4. DISCUSSION

Declarations

DISCLOSURES

ACKNOWLEDGEMENTS

References

Additional Declarations

Supplementary Files

Status:

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