AB0016 COMBINED GENOME-WIDE ASSOCIATION AND GENE-EXPRESSION META-ANALYSIS IDENTIFIES NOVEL PSORIASIS GENES
Authors: Mohammad Saeed
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background</h3> Psoriasis (Ps) is a common, inflammatory disorder affecting skin, joints and associated connective tissue, with significant genetic underpinnings. Multiple genome-wide association studies (GWAS) have been conducted with identification of several Ps loci. However, these only explain about a third of Ps genetic risk indicating that additional loci of modest effect remain to be discovered (1). <h3>Objectives</h3> Identify novel psoriasis genes that have functional consequences for psoriasis by altered gene-expression <h3>Methods</h3> Association clustering methods such as gene- and locus-based tests are more powerful than single variant analysis for identifying modest genetic effects (2, 3). Here, a dbGAP GWAS dataset (4) for Ps (pha002855: 1348 Ps cases and 1368 controls, genotyped for 448K SNPs) was analyzed using the locus-based algorithm, OASIS (3), to identify 13 highly significant loci other than the <i>HLA-C</i> locus. In these loci 50 genes were identified using SNIPPER, which were then subjected to gene expression analysis in three Ps GEO datasets. <h3>Results</h3> This genetic and functional analysis identified a total of 18 genes that were significantly associated and had altered expression in psoriasis skin. The most significant of these were two genes that were two-fold upregulated in Ps, <i>IL12B</i> (<i>P</i><i>=</i>9x10<sup>-11</sup>) and <i>TTC39B</i> (<i>P</i><i>=</i>3x10<sup>-12</sup>) and two genes that were repressed &lt;50%, <i>MAML2</i> (<i>P</i><i>=</i>8x10<sup>-19</sup>) and <i>EBF1</i> (<i>P</i><i>=</i>1x10<sup>-12</sup>). Interestingly, the expression of <i>IL23R</i> remained unaltered. Other genes that were significantly upregulated (1.5 – 2.0 fold) were <i>IL12RB2</i>, <i>TTC1</i> and <i>PSMD6</i>. Genes that were also significantly repressed (0.5 - 0.8 fold) were <i>SERBP1</i>, <i>ATXN7</i>, <i>PSIP1</i>, <i>ZNF385D</i>, <i>SIPA1L1</i>. <h3>Conclusion</h3> This combined genetic and functional meta-analysis elucidated novel genes, functional networks and pathways for psoriasis. These results will lead to important insights into the immunopathogenesis and treatment of psoriasis. <h3>References</h3> [1] Tsoi LC, Stuart PE, Tian C, et al. Large scale meta-analysis characterizes genetic architecture for common psoriasis associated variants. Nat Commun. 2017May24;8:15382. PMID: 28537254. [2] Luo L, Peng G, Zhu Y, et al. Genome-wide gene and pathway analysis. Eur J Hum Genet. 2010Sep;18(9):1045-53. PMID: 20442747. [3] Saeed M. Novel linkage disequilibrium clustering algorithm identifies new lupus genes on meta-analysis of GWAS datasets. Immunogenetics. 2017May;69(5):295-302. PMID: 28246883. [4] Nair RP, Duffin KC, Helms C, et al. Genome-wide scan reveals association of psoriasis with IL-23 and NF-kappaB pathways. Nat Genet. 2009Feb;41(2):199-204. PMID: 19169254. <h3>Disclosure of Interests</h3> Mohammad Saeed Shareholder of: Partner at ImmunoCure - laboratory, which performs Autoimmune antibody testing, Grant/research support from: Participation in EULAR 2019 Meeting is sponsored by High-Q Pharma Pak