Shared Genetic Risk Factors for Multiple Sclerosis/Psoriasis Suggest Involvement of Interleukin-17 and Janus Kinase-Signal Transducers and Activators of Transcription Signaling

Abstract

Objective: Psoriasis and multiple sclerosis (MS) are complex immune diseases that are mediated by T cells and share multiple comorbidities. Previous studies have suggested psoriatic patients are at higher risk of MS; however, causal relationships between the two conditions remain unclear. Through epidemiology and genetics, we provide a comprehensive understanding of the relationship, and share molecular factors between psoriasis and MS.

Methods: We used logistic regression, trans-disease meta-analysis and Mendelian randomization. Medical claims data were included from 30 million patients, including 141,544 with MS and 742,919 with psoriasis. We used genome-wide association study summary statistics from 11,024 psoriatic, 14,802 MS cases, and 43,039 controls for trans-disease meta-analysis, with additional summary statistics from 5 million individuals for Mendelian randomization.

Results: Psoriatic patients have a significantly higher risk of MS (4,637 patients with both diseases; odds ratio [OR] 1.07, p = 1.2 × 10^-5 ) after controlling for potential confounders. Using inverse variance and equally weighted trans-disease meta-analysis, we revealed >20 shared and opposing (direction of effect) genetic loci outside the major histocompatibility complex that showed significant genetic colocalization (in COLOC and COLOC-SuSiE v5.1.0). Co-expression analysis of genes from these loci further identified distinct clusters that were enriched among pathways for interleukin-17/tumor necrosis factor-α (OR >39, p < 1.6 × 10^-3 ) and Janus kinase-signal transducers and activators of transcription (OR 35, p = 1.1 × 10^-5 ), including genes, such as TNFAIP3, TYK2, and TNFRSF1A. Mendelian randomization found psoriasis as an exposure has a significant causal effect on MS (OR 1.04, p = 5.8 × 10^-3 ), independent of type 1 diabetes (OR 1.05, p = 4.3 × 10^-7 ), type 2 diabetes (OR 1.08, p = 2.3 × 10^-3 ), inflammatory bowel disease (OR 1.11, p = 1.6 × 10^-11 ), and vitamin D level (OR 0.75, p = 9.4 × 10^-3 ).

Interpretation: By investigating the shared genetics of psoriasis and MS, along with their modifiable risk factors, our findings will advance innovations in treatment for patients suffering from comorbidities. ANN NEUROL 2023;94:384-397.

Figure 1:. IVW trans-disease meta-analysis (TDMA).

Circular diagram including the following: a) Manhattan plot of shared (same direction of effect) psoriasis/MS TDMA signals, showing markers more significant in TDMA than for either trait. b) Manhattan plot of opposing (opposite direction of effect) psoriasis/MS trans-disease meta-analysis (TDMA) signals, showing markers more significant in TDMA than for either trait. Red dashed lines indicate the genome-wide significance (p<5×10⁻⁸) threshold for shared and opposing signals, respectively. Loci which meet this threshold and are suggestively significant (p<1×10⁻⁴) for both traits are highlighted in red (if identified through our original TDMA approach) or blue (for additional loci identified using GCTA-COJO). c) Density of H3K27ac active enhancer marks for B-cell centroblasts (the most enriched cell type among the TDMA loci, compared to other established loci for psoriasis and MS). The darker the color, the higher the proportion of regulatory marks overlapping each 2Mbp region. Genes reported by previous psoriasis and MS GWAS^,,– are labeled for each locus. d) Links between genes, according to co-expression in L1000 assay perturbation experiments from NIH’s Library of Integrated Network-Based Cellular Signatures (LINCS). Each link has a random color, with transparency (alpha) values set proportional to the log-scaled number of experiments in which at least one gene from a locus is co-expressed with at least one gene from another locus, such that more opaque links represent pairs of loci with genes co-expressed in more experiments.

Figure 2:. Regional association plots for four loci identified by IVW TDMA.

For each of the following loci, the lead TDMA marker is indicated in purple and the other markers are colored according to their LD with the lead marker: a) 6q25.3 opposing locus, with rs2451279 lead marker; b) 7p14.1 shared locus, with rs17259252 lead marker; c) 10q22.3 opposing locus, with rs1108618 lead marker; d) 13q14.2 shared locus, with rs9591325 lead marker.

Figure 3:. Mendelian randomization (MR) results for the effects of psoriasis and other comorbidities on multiple sclerosis.

Forest plots generated from the results of six MR techniques (a-f). Abbreviations are as follows: T1D, type 1 diabetes; T2D, type 2 diabetes; CAD, coronary artery disease; RA, rheumatoid arthritis; IBD, inflammatory bowel disease; VitD, vitamin D (25OHD); BMI, body mass index; Smoke, cigarettes per day; Drink, drinks per week; p, p-value; OR, odds ratio.