Premium
Comparative Genetic Analysis of Psoriatic Arthritis and Psoriasis for the Discovery of Genetic Risk Factors and Risk Prediction Modeling
Author(s) -
Soomro Mehreen,
Stadler Michael,
Dand Nick,
Bluett James,
Jadon Deepak,
Jalalinajafabadi Farideh,
Duckworth Michael,
Ho Pauline,
MarzoOrtega 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
Publication year - 2022
Publication title -
arthritis and rheumatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.106
H-Index - 314
eISSN - 2326-5205
pISSN - 2326-5191
DOI - 10.1002/art.42154
Subject(s) - medicine , genome wide association study , heritability , psoriatic arthritis , single nucleotide polymorphism , genetic model , psoriasis , snp , oncology , genetics , biology , immunology , genotype , gene
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.