title: A genetic risk score combining ten psoriasis risk loci improves disease prediction.
abstract: Psoriasis is a chronic, immune-mediated skin disease affecting 2-3% of Caucasians. Recent genetic association studies have identified multiple psoriasis risk loci; however, most of these loci contribute only modestly to disease risk. In this study, we investigated whether a genetic risk score (GRS) combining multiple loci could improve psoriasis prediction. Two approaches were used: a simple risk alleles count (cGRS) and a weighted (wGRS) approach. Ten psoriasis risk SNPs were genotyped in 2815 case-control samples and 858 family samples. We found that the total number of risk alleles in the cases was significantly higher than in controls, mean 13.16 (SD 1.7) versus 12.09 (SD 1.8), p = 4.577×10(-40). The wGRS captured considerably more risk than any SNP considered alone, with a psoriasis OR for high-low wGRS quartiles of 10.55 (95% CI 7.63-14.57), p = 2.010×10(-65). To compare the discriminatory ability of the GRS models, receiver operating characteristic curves were used to calculate the area under the curve (AUC). The AUC for wGRS was significantly greater than for cGRS (72.0% versus 66.5%, p = 2.13×10(-8)). Additionally, the AUC for HLA-C alone (rs10484554) was equivalent to the AUC for all nine other risk loci combined (66.2% versus 63.8%, p = 0.18), highlighting the dominance of HLA-C as a risk locus. Logistic regression revealed that the wGRS was significantly associated with two subphenotypes of psoriasis, age of onset (p = 4.91×10(-6)) and family history (p = 0.020). Using a liability threshold model, we estimated that the 10 risk loci account for only 11.6% of the genetic variance in psoriasis. In summary, we found that a GRS combining 10 psoriasis risk loci captured significantly more risk than any individual SNP and was associated with early onset of disease and a positive family history. Notably, only a small fraction of psoriasis heritability is captured by the common risk variants identified to date.
authors.affiliation: Department of Dermatology, University of California San Francisco, San Francisco, California, United States of America.
authors.forename: Haoyan
authors.initials: H
authors.lastname: Chen
authors.forename: Annie
authors.initials: A
authors.lastname: Poon
authors.forename: Celestine
authors.initials: C
authors.lastname: Yeung
authors.forename: Cynthia
authors.initials: C
authors.lastname: Helms
authors.forename: Jennifer
authors.initials: J
authors.lastname: Pons
authors.forename: Anne M
authors.initials: AM
authors.lastname: Bowcock
authors.forename: Pui-Yan
authors.initials: PY
authors.lastname: Kwok
authors.forename: Wilson
authors.initials: W
authors.lastname: Liao
mesh_terms: D019540:Area Under Curve; D016022:Case-Control Studies; D005192:Family Health; D005260:Female; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D008297:Male; D008957:Models, Genetic; D015233:Models, Statistical; D011565:Psoriasis / Q000175:diagnosis* / Q000235:genetics*; D012372:ROC Curve; D012044:Regression Analysis; D012306:Risk