Genome-wide Association Analysis of Psoriatic Arthritis and Cutaneous Psoriasis Reveals Differences in Their Genetic Architecture  Philip E. Stuart, Rajan P.

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Genome-wide Association Analysis of Psoriatic Arthritis and Cutaneous Psoriasis Reveals Differences in Their Genetic Architecture  Philip E. Stuart, Rajan P. Nair, Lam C. Tsoi, Trilokraj Tejasvi, Sayantan Das, Hyun Min Kang, Eva Ellinghaus, Vinod Chandran, Kristina Callis-Duffin, Robert Ike, Yanming Li, Xiaoquan Wen, Charlotta Enerbäck, Johann E. Gudjonsson, Sulev Kõks, Külli Kingo, Tõnu Esko, Ulrich Mrowietz, Andre Reis, H. Erich Wichmann, Christian Gieger, Per Hoffmann, Markus M. Nöthen, Juliane Winkelmann, Manfred Kunz, Elvia G. Moreta, Philip J. Mease, Christopher T. Ritchlin, Anne M. Bowcock, Gerald G. Krueger, Henry W. Lim, Stephan Weidinger, Michael Weichenthal, John J. Voorhees, Proton Rahman, Peter K. Gregersen, Andre Franke, Dafna D. Gladman, Gonçalo R. Abecasis, James T. Elder  The American Journal of Human Genetics  Volume 97, Issue 6, Pages 816-836 (December 2015) DOI: 10.1016/j.ajhg.2015.10.019 Copyright © 2015 The American Society of Human Genetics Terms and Conditions

Figure 1 Manhattan Plots of Association Results for Meta-analysis of Six Discovery Studies Each circle represents the −log10(p) of the imputed variants, including SNPs and indels. Thresholds of suggestive (p = 1 × 10−6) and GW (p = 5 × 10−8) significance are delineated with blue and red lines, respectively. All chromosomal regions achieving GW significance are highlighted in green and labeled with their leading candidate susceptibility gene. Font color of the candidate genes indicates published GW significant associations with psoriasis and its cutaneous and joint subphenotypes: purple indicates known PsA, PsC, and PsV association, red indicates known PsA and PsV association, cyan indicates known PsC and PsV association, black indicates known PsV association, and green indicates possible new psoriasis association. We tested association for four binary phenotypes: PsV case versus control subjects (A), PsA case versus control subjects (B), PsC case versus control subjects (C), and PsA case versus PsC case subjects (D). The American Journal of Human Genetics 2015 97, 816-836DOI: (10.1016/j.ajhg.2015.10.019) Copyright © 2015 The American Society of Human Genetics Terms and Conditions

Figure 2 Comparison of PsC and PsA Associations for the TNFRSF9 and LCE3C/B Regions Negative log10-transformed p values from meta-analyses of association for the six discovery datasets are shown for 800-kb regions encompassing genes TNFRSF9 (A−C) and LCE3C and LCE3B (D−F). For each region the SNP with the most significant association for the comparison of PsC case subjects with unaffected control subjects is labeled. The color of each symbol denotes the strength of LD (r2 coefficient) with the index SNP. (A) and (D) Shown are association results for PsA case versus control subjects (A, D), for PsC case versus control subjects (B, E), and for a conservative parametric test of the difference in log(OR) values from the PsA versus control and PsC versus control subjects (C, F) comparisons. The bottom two panels give the physical positions of known genes in each region. The American Journal of Human Genetics 2015 97, 816-836DOI: (10.1016/j.ajhg.2015.10.019) Copyright © 2015 The American Society of Human Genetics Terms and Conditions

Figure 3 Comparison of PsA and PsC Associations for the IL23R and TNFAIP3 Regions Negative log10-transformed p values from meta-analyses of association for the six discovery datasets are shown for 800-kb regions encompassing genes IL23R (A−C) and TNFAIP3 (D−F). For each region two reference SNPs are labeled—the red and blue diamonds denote the variant that was most significantly associated for a test of PsA case versus control subjects or PsC case versus control subjects, respectively. For all other plotted variants, the color and shape of the symbol denotes which index SNP the variant is in highest LD with (red circles for the PsA index, blue triangles for the PsC index), and the intensity of the color indicates the magnitude of the pairwise LD r2 coefficient. Shown are association results for PsA case versus control subjects (A, D) and for PsC case versus control subjects (B, E). Results for a conservative parametric test of the difference in log(OR) values from the PsA versus control and PsC versus control comparisons shown in (C) and (F). The bottom two panels give the physical positions of known genes in each region. The American Journal of Human Genetics 2015 97, 816-836DOI: (10.1016/j.ajhg.2015.10.019) Copyright © 2015 The American Society of Human Genetics Terms and Conditions

Figure 4 Liability Plots for Five Regions with Multiple Independent Psoriasis Variants Liability plots for five genomic regions—near IL23R (A), IFIH1 (B), IL12B (C), TNFAIP3 (D), and NOS2 (E)—with multiple independent variants associated with psoriasis or its cutaneous and joint subphenotypes. Percent variance in disease liability explained by each variant was computed and adjusted for LD dependencies with other variants in the region by the method of Ho et al.69 The label above each plotted symbol indicates both the associated phenotype (P = PsV, A = PsA, C = PsC) and the round of conditional association analysis (0 = unconditional, 1 = first round conditional, 2 = second round conditional, etc.). Grey fill for a plotted symbol indicates that the association ORs for the variant in the six-study meta-analysis of PsA case versus unaffected control subjects and PsC case versus unaffected control subjects were not significantly different; red fill indicates a significantly larger OR for the PsA versus control comparison. LD blocks, shown with two alternating shades of green, were delineated by the D′ confidence interval method68 using genotypes for all SNPs with MAF ≥ 0.05 in the 379 individuals of European ancestry in phase 1 of the 1000 Genomes Project.65 The bands for the r2 clumps, shown in two shades of purple when necessary, encompass clusters of markers with an average pairwise r2 LD coefficient ≥ 0.3. The American Journal of Human Genetics 2015 97, 816-836DOI: (10.1016/j.ajhg.2015.10.019) Copyright © 2015 The American Society of Human Genetics Terms and Conditions