LAUSR

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 shared molecular factors between psoriasis and MS. METHODS We used logistic regression, trans-disease meta-analysis (TDMA) and Mendelian randomization (MR). Medical claims data was included from 30 million patients, including 141,544 with MS and 742,919 with psoriasis. We used GWAS summary statistics from 11,024 psoriatic, 14,802 MS cases and 43,039 controls for TDMA, with additional summary statistics from 5 million individuals for MR. RESULTS Psoriatic patients have significantly higher risk of MS (4,637 patients with both diseases; OR=1.07, p=1.2×10-5 ), after controlling for potential confounders. Using inverse variance and equally weighted TDMA, we revealed more than 20 shared and opposing (direction of effect) genetic loci outside the MHC which show significant genetic colocalization (in COLOC and COLOC-SuSiE v5.1.0). Co-expression analysis of genes from these loci further identified distinct clusters which were enriched among pathways for IL-17/TNFα (p<1.6×10-3 , OR>39) and JAK-STAT (p=1.1×10-5 , OR=35), including genes such as TNFAIP3, TYK2 and TNFRSF1A. MR found psoriasis as an exposure has a significant causal effect on MS (OR=1.04, p=5.8×10-3 ), independent of T1D (p=4.3×10-7 , OR=1.05), T2D (p=2.3×10-3 , OR=1.08), IBD (p=1.6×10-11 , OR=1.11) and vitamin D level (p=9.4×10-3 , OR=0.75). 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. This article is protected by copyright. All rights reserved.