Comparative Genetic Analysis of Psoriatic Arthritis and Psoriasis for the Discovery of Genetic Risk Factors and Risk Prediction Modeling

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 1535

Association between psoriatic disease and lifestyle factors and comorbidities: cross-sectional analysis and Mendelian randomization

“…Genome-wide association studies (GWAS) for all traits are summarised in Table 1 ; additional details of demographics, genotyping and phenotype definitions for each study are available in each original publication referenced. For PsA as the outcome, we used existing summary data from a GWAS comprising 3609 cases and 9192 controls; the majority of cases satisfied the CASPAR classification criteria, but some were recruited prior to its publication [ 13 ]. PsA data were independent of the above observational analyses.…”

“…We additionally estimated the ‘reverse’ effects of psoriatic disease (as the ‘exposure’) on lifestyle factors or comorbidities. To instrument PsA or psoriasis, we used independent GWAS-significant variants reported in Soomro et al [ 13 ] and Tsoi et al [ 14 ], respectively ( Supplementary Table S1 , available at Rheumatology online). The Tsoi psoriasis GWAS differed from our UK Biobank GWAS in having a larger sample size (it could not be used above as the outcome because summary statistics were not available).…”

Using Polygenic Risk Scores to Aid Diagnosis of Patients With Early Inflammatory Arthritis: Results From the Norfolk Arthritis Register

“…However, the PPV was modest, which demonstrates that genetics alone cannot accurately suggest or make diagnoses; this is not unexpected given that common rheumatologic conditions are typically only between 60% and 90% heritable. [12][13][14][15][16] It is important to note that the tool itself, and therefore its current performance, is directly linked to how much is known about the genetic risks of the diseases assessed, so as more susceptibility loci are discovered for each disease, performance may improve further. Furthermore, integrating clinical risk factors such as demographics, serology, and comorbidities with PRS has the potential to improve predictive performance, including PPV, as has been demonstrated in studies in atherosclerotic cardiovascular disease.…”

Separating the effects of childhood and adult body size on inflammatory arthritis: a Mendelian randomisation study

“… 21 The PsA GWAS included 3609 cases and 9192 controls; the majority satisfied the ClASsifiaction criteria for Psoriatic ARthritis criteria, but some were recruited prior to its publication. 22 Genetic associations for gout were taken from a meta-analysis of 13 179 cases and 763 813 controls. 23 The SLE GWAS comprised 5201 cases (ACR classification criteria) and 9066 controls.…”