Psoriasis and COVID-19: A bidirectional Mendelian randomization study

To the Editor: There is a bidirectional link between psoriasis and infection, certain infections could trigger psoriasis and psoriasis is associated with an increased risk of serious infection.¹ Currently, there is limited evidence on the association between psoriasis and COVID-19.² In a recent Mendelian randomization (MR) study in the Journal of American Association of Dermatology, Xiaoyu Gu et al³ suggested that genetic predisposition to psoriasis was associated with increased susceptibility to COVID-19. Here, we conducted an updated MR analysis (Fig 1 ) including genome-wide summary statistics for psoriasis with a larger sample size and doctor-diagnosis of psoriasis, the latest release of COVID-19 genome-wide association study (GWAS) and several sensitivity analyses to examine the MR assumptions.

Fig 1.

Study design overview and assumptions of the Mendelian randomization (MR) design. Dashed lines represent potential pleiotropic or direct causal effects between variables that would violate MR assumptions. Assumption 1: genetic variants are associated with the exposure; Assumption 2: genetic variants are not associated with any confounders; and Assumption 3: genetic variants influence risk only through the exposure and not through any alternative pathways. The MR design can reduce residual confounding and reverse causality, thereby reinforcing the causal inference of an exposure-outcome association. The basis of this is that genetic variants, selected as instrumental variables for studying the effect of modifying the exposure, are randomly allocated at conception and are, therefore, less vulnerable to confounding from environmental factors and reverse causation. SNP, Single nucleotide polymorphism.

Summary statistics for psoriasis were obtained from the largest GWAS meta-analysis of European ancestry, with cases defined as dermatologist-diagnosed psoriasis with 13,229 cases and 21,543 controls (after excluding the 23 and Me cohort)⁴ (Supplementary Table I, available via Mendeley at https://doi.org/10.17632/hff49h4zpn.1). For COVID-19, the latest available data (round 7) from the COVID-19 Host Genetics Initiative were gathered (www.covid19hg.org/results/r7/) incorporating in the analysis of all the available phenotypes.⁵ The inverse variance weighted (IVW) method was used as the primary method and sensitivity analyses were conducted including weighted median, MR-Egger, MR-Pleiotropy RESidual Sum and Outlier (PRESSO), and weighted mode. A Bonferroni corrected significance level P < .05/3 (=0.017) was considered statistically significant and MR analysis was performed with R version 4.1.2 using the “TwoSampleMR” and “MRPRESSO” packages.

The MR analysis did not find any association between genetical predisposition to psoriasis with increased susceptibility to COVID-19 (COVID-19 vs population; odds ratio [OR]_IVW = 0.994; 95% confidence interval [CI], 0.98 to 1.009; P = .465); (COVID-19 hospitalized vs population; OR_IVW = 1.003; 95% CI, 0.965 to 1.043; P = .876); and (COVID-19 severe vs population; OR_IVW = 1.009; 95% CI, 0.951 to 1.07; P = .764) in accordance with the sensitivity analyses (Supplementary Table II, available via Mendeley at https://doi.org/10.17632/hff49h4zpn.1). There was little evidence for horizontal pleiotropy (MR-Egger intercept P = .499, P = .106, & P = .106). Effect estimates for the association between exposure and outcome are in Supplementary Table II, available via Mendeley at https://doi.org/10.17632/hff49h4zpn.1. Even after correcting for outliers, the MR-PRESSO did not show any association with any COVID-19 phenotype (Supplementary Table II, available via Mendeley at https://doi.org/10.17632/hff49h4zpn.1) and the leave-one-single nucleotide polymorphism out analysis did not reveal any influential single nucleotide polymorphism (Supplementary Tables III and IV, available via Mendeley at https://doi.org/10.17632/hff49h4zpn.1). When we evaluated the bidirectional association, genetic predisposition to COVID-19 did not elevate the risk of developing psoriasis (Supplementary Table II, available via Mendeley at https://doi.org/10.17632/hff49h4zpn.1).

Our results do not support the previous study conducted by Xiaoyu Gu et al³ There are several reasons for this discrepancy. Firstly, the GWAS of psoriasis by the Neale laboratory, which Xiaoyu Gu et al³ used, had a limited sample size (3871 vs 13,229 included here) and was proven to misclassification due to the self-reported diagnosis of psoriasis. Secondly, Xiaoyu Gu et al³ did not take advantage of the latest available data for COVID-19 during their analysis (round 6, release date: June 15, 2021) which included a substantially higher number of cases. Most importantly, the phenotype used by Xiaoyu Gu et al³ was just “COVID-19 vs population” in comparison to the more robust phenotype of “COVID-19 hospitalized vs population” and “COVID-19 severe vs population” used in our analyses. We have also confirmed our findings with several sensitivity analyses none of which suggested a causal association between psoriasis and the severity of COVID-19 disease. In conclusion, our study does not support that genetic predisposition to psoriasis is associated with higher susceptibility to being infected, hospitalized, or developing severe COVID-19 in Europeans.

Conflicts of interest

None disclosed.