Abstract
Abstract Psoriasis is a common inflammatory skin disease with heterogeneous presentation. Up to 30% of affected individuals have severe disease with a greater surface area of skin involvement, co-morbidity burden and impact on quality of life. Prognostic biomarkers of psoriasis severity could improve the allocation of clinical resources and enable earlier intervention to prevent disease progression, and a genetic biomarker would be cost-effective, stable over time, and unaffected by treatment or comorbidity. Psoriasis severity was studied in four European population-based biobanks and classified based on the level of clinical intervention received, with criteria for severe disease including hospitalization due to psoriasis, use of systemic immunomodulating therapy or phototherapy. Common genetic variants, polygenic risk scores and established epidemiological risk factors were tested for association with severe psoriasis in each of the constituent biobanks and combined through meta-analysis. The distribution of psoriasis polygenic risk was also evaluated in an independent cohort of 4151 participants in the UK-based severe psoriasis registry, BSTOP. In the population-based datasets, 9738 of 44 904 individuals with psoriasis (21.7%) were classified as having severe disease. Genetic variants within the major histocompatibility complex and the TNIP1 and IL12B psoriasis susceptibility loci were associated with severe disease at genome-wide significance (P < 5.0 × 10−8). Furthermore, a strong positive correlation was observed between psoriasis susceptibility and severity effect sizes across all psoriasis susceptibility loci. An individual’s genetic liability to psoriasis as measured with a polygenic risk score (PRS) strongly associated with disease severity, with a magnitude of effect comparable to established severity risk factors such as obesity and smoking. The top 5% of psoriasis cases by genetic liability were 1.23–2.00 times as likely than the average psoriasis case to have severe disease. Psoriasis cases in the BSTOP severe disease registry were 3.10-fold enriched for a PRS that exceeded the 95th percentile established among UK Biobank psoriasis cases. The psoriasis susceptibility PRS demonstrates utility and may be as effective as established epidemiological factors, as a stratification tool to identify those individuals that are at the greatest risk of severe disease. Further work is needed to determine whether high-risk individuals may benefit most from early intervention.
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