Evidence for the gut-skin axis: Common genetic structures in inflammatory bowel disease and psoriasis

Abstract

Background: Inflammatory bowel disease (IBD) and psoriasis (Ps) are common immune-mediated diseases that exhibit clinical comorbidity, possibly due to a common genetic structure. However, the exact mechanism remains unknown.

Methods: The study population consisted of IBD and Ps genome-wide association study (GWAS) data. Genetic correlations were first evaluated. Then, the overall evaluation employed LD score regression (LDSC), while the local assessment utilized heritability estimation from summary statistics (HESS). Causality assessment was conducted through two-sample Mendelian randomization (2SMR), and genetic overlap analysis utilized the conditional false discovery rate/conjunctional FDR (cond/conjFDR) method. Finally, LDSC applied to specifically expressed genes (LDSC-SEG) was performed at the tissue level. For IBD and Ps-specific expressed genes, genetic correlation, causality, shared genetics, and trait-specific associated tissues were methodically examined.

Results: At the genomic level, both overall and local genetic correlations were found between IBD and Ps. MR analysis indicated a positive causal relationship between Ps and IBD. The conjFDR analysis with a threshold of < 0.01 identified 43 loci shared between IBD and Ps. Subsequent investigations into disease-associated tissues indicated a close association of IBD and Ps with whole blood, lung, spleen, and EBV-transformed lymphocytes.

Conclusion: The current research offers a novel perspective on the association between IBD and Ps. It contributes to an enhanced comprehension of the genetic structure and mechanisms of comorbidities in both diseases.

Keywords: GWAS; genetic risk loci; genetic structure; gut-skin axis; psoriasis.

FIGURE 1

Flowchart of the study. IBD, inflammatory bowel disease; Ps, Psoriasis.

FIGURE 2

MR Analysis process and acquisition of valid IV steps. IBD, inflammatory bowel disease; IV, instrumental variables; Ps, Psoriasis.

FIGURE 3

HESS analysis of IBD and Ps. The top and middle sections display local genetic correlations and covariances between IBD and Ps, respectively. Genetic correlation, denoted as rg, is the statistical measure of the degree to which two traits share common genetic influence. The coloured bars indicate loci with significant local genetic correlations and covariances. The bottom portion represents the local SNP heritability of each trait (IBD and Ps), with coloured bars denoting loci with significant local SNP heritability. Heritability refers to the proportion of the total variance in a trait that can be attributed to genetic variation. HESS, heritability estimation from summary statistics; IBD, inflammatory bowel disease; Ps, psoriasis; SNP, single‐nucleotide polymorphism.

FIGURE 4

Results of MR analyses. (A) Scatter plot illustrating the causal effect of IBD on Ps. Each point represents a genetic variant, and the slope of each line corresponds to the effect estimates obtained by different MR methods. (B) Forest plot displaying the results of the leave‐one‐out analysis. Each genetic variant was systematically removed to assess whether the overall MR estimates were influenced by a single genetic variant. IBD, inflammatory bowel disease; MR, Mendelian randomization; Ps, psoriasis.

FIGURE 5

Conditional quantile‐quantile plot. The dashed line indicates the expected line under the null hypothesis, and the deflection to the left indicates the degree of pleiotropic enrichment. IBD, inflammatory bowel disease; Ps, Psoriasis.

FIGURE 6

ConjFDR Manhattan plot. The shared risk loci between IBD and Ps were marked. The statistically significant causality is defined to be conjFDR  < 0.01. IBD, inflammatory bowel disease; Ps, Psoriasis.

FIGURE 7

The Results of Enrichment analysis. (A) GO enrichment analysis at biological process. (B) GO enrichment analysis at molecular function. (C) GO enrichment analysis at cell composition. (D) KEGG analysis. GO; Gene Ontology; KEGG, Kyoto Encyclopedia of Genes and Genomes.

FIGURE 8

Tissues enrichment results of IBD (A) and Ps (B) using gene expression data of 53 tissues from GTEx. IBD, inflammatory bowel disease; Ps, Psoriasis.