Comparative Genetic Analysis of Psoriatic Arthritis and Psoriasis for the Discovery of Genetic Risk Factors and Risk Prediction Modeling. Issue 9 (4th August 2022)

• Record Type: Journal Article
• Authors: Soomro, Mehreen; Stadler, Michael; Dand, Nick; Bluett, James; Jadon, Deepak; Jalali‐najafabadi, Farideh; Duckworth, Michael; Ho, Pauline; Marzo‐Ortega, Helena; Helliwell, Philip S.; Ryan, Anthony W.; Kane, David; Korendowych, Eleanor; Simpson, Michael A.; Packham, Jonathan; McManus, Ross; Gabay, Cem; Lamacchia, Céline; Nissen, Michael J.; Brown, Matthew A.; Verstappen, Suzanne M. M.; Van Staa, Tjeerd; Barker, Jonathan N.; Smith, Catherine H.; FitzGerald, Oliver; McHugh, Neil; Warren, Richard B.; Bowes, John; Barton, Anne
• Other Names: Chalmers Robert investigator.; Flohr Carsten investigator.; Watson Karen investigator.; Prieto‐Merino David investigator.; Alabas Oras investigator.; Barker Jonathan investigator.; Becher Gabrielle investigator.; Bewley Anthony investigator.; Burden David investigator.; Morrison Simon investigator.; Laws Phil investigator.; Evans Ian investigator.; Griffiths Christopher investigator.; Ahmed Shehnaz investigator.; Kirby Brian investigator.; Kleyn Elise investigator.; Lawson Linda investigator.; Mackenzie Teena investigator.; McPherson Tess investigator.; McElhone Kathleen investigator.; Murphy Ruth investigator.; Ormerod Anthony investigator.; Owen Caroline investigator.; Reynolds Nick investigator.; Rashid Amir investigator.; Smith Catherine investigator.; Warren Richard investigator.; Burden David investigator.; Smith Catherine investigator.; Siebert Stefan investigator.; Brown Sara investigator.; McAteer Helen investigator.; Schofield Julia investigator.; Dand Nick investigator.;
• Is Part Of: Arthritis & rheumatology. Volume 74:Issue 9(2022)
• Page Start: 1535
• Page End: 1543
• Publication Date: 2022-08-04
• Subjects: Arthritis -- Periodicals; Rheumatism -- Periodicals; 616.72
• DOI: 10.1002/art.42154
• Languages: English
• ISSNs: 2326-5191

Abstract

Abstract : Objectives: Psoriatic arthritis (PsA) has a strong genetic component, and the identification of genetic risk factors could help identify the ~30% of psoriasis patients at high risk of developing PsA. Our objectives were to identify genetic risk factors and pathways that differentiate PsA from cutaneous‐only psoriasis (PsC) and to evaluate the performance of PsA risk prediction models. Methods: Genome‐wide meta‐analyses were conducted separately for 5, 065 patients with PsA and 21, 286 healthy controls and separately for 4, 340 patients with PsA and 6, 431 patients with PsC. The heritability of PsA was calculated as a single‐nucleotide polymorphism (SNP)–based heritability estimate (h 2 SNP ) and biologic pathways that differentiate PsA from PsC were identified using Priority Index software. The generalizability of previously published PsA risk prediction pipelines was explored, and a risk prediction model was developed with external validation. Results: We identified a novel genome‐wide significant susceptibility locus for the development of PsA on chromosome 22q11 (rs5754467; P = 1.61 × 10 −9 ), and key pathways that differentiate PsA from PsC, including NF‐κB signaling (adjusted P = 1.4 × 10 −45 ) and Wnt signaling (adjusted P = 9.5 × 10 −58 ). The heritability of PsA in this cohort was found to be moderate (h 2 SNP = 0.63), which was similar to the heritability of PsC (h 2 SNP = 0.61). We observed modest performance of published classification pipelines (maximum area under the curve 0.61), with similar performance of a risk model derived using the current data. Conclusion: Key biologic pathways associated with the development of PsA were identified, but the investigation of risk classification revealed modest utility in the available data sets, possibly because many of the PsC patients included in the present study were receiving treatments that are also effective in PsA. Future predictive models of PsA should be tested in PsC patients recruited from primary care.