A deletion at ADAMTS9-MAGI1 locus is associated with psoriatic arthritis risk.

Copy number variants (CNVs) have been associated with the risk to develop multiple autoimmune diseases. Our objective was to identify CNVs associated with the risk to develop psoriatic arthritis (PsA) using a genome-wide analysis approach. A total of 835 patients with PsA and 1498 healthy controls were genotyped for CNVs using the Illumina HumanHap610 BeadChip genotyping platform. Genomic CNVs were characterised using CNstream analysis software and analysed for association using the χ(2) test. The most significant genomic CNV associations with PsA risk were independently tested in a validation sample of 1133 patients with PsA and 1831 healthy controls. In order to test for the specificity of the variants with PsA aetiology, we also analysed the association to a cohort of 822 patients with purely cutaneous psoriasis (PsC). A total of 165 common CNVs were identified in the genome-wide analysis. We found a highly significant association of an intergenic deletion between ADAMTS9 and MAGI1 genes on chromosome 3p14.1 (p=0.00014). Using the independent patient and control cohort, we validated the association between ADAMTS9-MAGI1 deletion and PsA risk (p=0.032). Using next-generation sequencing, we characterised the 26 kb associated deletion. Finally, analysing the PsC cohort we found a lower frequency of the deletion compared with the PsA cohort (p=0.0088) and a similar frequency to that of healthy controls (p>0.3). The present genome-wide scan for CNVs associated with PsA risk has identified a new deletion associated with disease risk and which is also differential from PsC risk.

Julià A ，Pinto JA ，Gratacós J ，Queiró R ，Ferrándiz C ，Fonseca E ，Montilla C ，Torre-Alonso JC ，Puig L ，Pérez Venegas JJ ，Fernández Nebro A ，Fernández E ，Muñoz-Fernández S ，Daudén E ，González C ，Roig D ，Sánchez Carazo JL ，Zarco P ，Erra A ，López Estebaranz JL ，Rodríguez J ，Ramírez DM ，de la Cueva P ，Vanaclocha F ，Herrera E ，Castañeda S ，Rubio E ，Salvador G ，Díaz-Torné C ，Blanco R ，Willisch Domínguez A ，Mosquera JA ，Vela P ，Tornero J ，Sánchez-Fernández S ，Corominas H ，Ramírez J ，López-Lasanta M ，Tortosa R ，Palau N ，Alonso A ，García-Montero AC ，Gelpí JL ，Codó L ，Day K ，Absher D ，Myers RM ，Cañete JD ，Marsal S ... -  《-》

Genome-wide association and targeted analysis of copy number variants with psoriatic arthritis in German patients.

Uebe S ，Ehrlicher M ，Ekici AB ，Behrens F ，Böhm B ，Homuth G ，Schurmann C ，Völker U ，Jünger M ，Nauck M ，Völzke H ，Traupe H ，Krawczak M ，Burkhardt H ，Reis A ，Hüffmeier U ... -  《BMC Medical Genetics》

Genome-wide Association Analysis of Psoriatic Arthritis and Cutaneous Psoriasis Reveals Differences in Their Genetic Architecture.

Psoriasis vulgaris (PsV) is a common inflammatory and hyperproliferative skin disease. Up to 30% of people with PsV eventually develop psoriatic arthritis (PsA), an inflammatory musculoskeletal condition. To discern differences in genetic risk factors for PsA and cutaneous-only psoriasis (PsC), we carried out a genome-wide association study (GWAS) of 1,430 PsA case subjects and 1,417 unaffected control subjects. Meta-analysis of this study with three other GWASs and two targeted genotyping studies, encompassing a total of 9,293 PsV case subjects, 3,061 PsA case subjects, 3,110 PsC case subjects, and 13,670 unaffected control subjects of European descent, detected 10 regions associated with PsA and 11 with PsC at genome-wide (GW) significance. Several of these association signals (IFNLR1, IFIH1, NFKBIA for PsA; TNFRSF9, LCE3C/B, TRAF3IP2, IL23A, NFKBIA for PsC) have not previously achieved GW significance. After replication, we also identified a PsV-associated SNP near CDKAL1 (rs4712528, odds ratio [OR] = 1.16, p = 8.4 × 10(-11)). Among identified psoriasis risk variants, three were more strongly associated with PsC than PsA (rs12189871 near HLA-C, p = 5.0 × 10(-19); rs4908742 near TNFRSF9, p = 0.00020; rs10888503 near LCE3A, p = 0.0014), and two were more strongly associated with PsA than PsC (rs12044149 near IL23R, p = 0.00018; rs9321623 near TNFAIP3, p = 0.00022). The PsA-specific variants were independent of previously identified psoriasis variants near IL23R and TNFAIP3. We also found multiple independent susceptibility variants in the IL12B, NOS2, and IFIH1 regions. These results provide insights into the pathogenetic similarities and differences between PsC and PsA.

Stuart PE ，Nair RP ，Tsoi LC ，Tejasvi T ，Das S ，Kang HM ，Ellinghaus E ，Chandran V ，Callis-Duffin K ，Ike R ，Li Y ，Wen X ，Enerbäck C ，Gudjonsson JE ，Kõks S ，Kingo K ，Esko T ，Mrowietz U ，Reis A ，Wichmann HE ，Gieger C ，Hoffmann P ，Nöthen MM ，Winkelmann J ，Kunz M ，Moreta EG ，Mease PJ ，Ritchlin CT ，Bowcock AM ，Krueger GG ，Lim HW ，Weidinger S ，Weichenthal M ，Voorhees JJ ，Rahman P ，Gregersen PK ，Franke A ，Gladman DD ，Abecasis GR ，Elder JT ... -  《-》

Genetic variation at the glycosaminoglycan metabolism pathway contributes to the risk of psoriatic arthritis but not psoriasis.

Psoriatic arthritis (PsA) is a chronic inflammatory arthritis affecting up to 30% of patients with psoriasis (Ps). To date, most of the known risk loci for PsA are shared with Ps, and identifying disease-specific variation has proven very challenging. The objective of the present study was to identify genetic variation specific for PsA. We performed a genome-wide association study in a cohort of 835 patients with PsA and 1558 controls from Spain. Genetic association was tested at the single marker level and at the pathway level. Meta-analysis was performed with a case-control cohort of 2847 individuals from North America. To confirm the specificity of the genetic associations with PsA, we tested the associated variation using a purely cutaneous psoriasis cohort (PsC, n=614) and a rheumatoid arthritis cohort (RA, n=1191). Using network and drug-repurposing analyses, we further investigated the potential of the PsA-specific associations to guide the development of new drugs in PsA. We identified a new PsA risk single-nucleotide polymorphism at B3GNT2 locus (p=1.10e-08). At the pathway level, we found 14 genetic pathways significantly associated with PsA (pFDR<0.05). From these, the glycosaminoglycan (GAG) metabolism pathway was confirmed to be disease-specific after comparing the PsA cohort with the cohorts of patients with PsC and RA. Finally, we identified candidate drug targets in the GAG metabolism pathway as well as new PsA indications for approved drugs. These findings provide insights into the biological mechanisms that are specific for PsA and could contribute to develop more effective therapies.

Aterido A ，Cañete JD ，Tornero J ，Ferrándiz C ，Pinto JA ，Gratacós J ，Queiró R ，Montilla C ，Torre-Alonso JC ，Pérez-Venegas JJ ，Fernández Nebro A ，Muñoz-Fernández S ，González CM ，Roig D ，Zarco P ，Erra A ，Rodríguez J ，Castañeda S ，Rubio E ，Salvador G ，Díaz-Torné C ，Blanco R ，Willisch Domínguez A ，Mosquera JA ，Vela P ，Sánchez-Fernández SA ，Corominas H ，Ramírez J ，de la Cueva P ，Fonseca E ，Fernández E ，Puig L ，Dauden E ，Sánchez-Carazo JL ，López-Estebaranz JL ，Moreno D ，Vanaclocha F ，Herrera E ，Blanco F ，Fernández-Gutiérrez B ，González A ，Pérez-García C ，Alperi-López M ，Olivé Marques A ，Martínez-Taboada V ，González-Álvaro I ，Sanmartí R ，Tomás Roura C ，García-Montero AC ，Bonàs-Guarch S ，Mercader JM ，Torrents D ，Codó L ，Gelpí JL ，López-Corbeto M ，Pluma A ，López-Lasanta M ，Tortosa R ，Palau N ，Absher D ，Myers R ，Marsal S ，Julià A ... -  《-》

A genome-wide association study of psoriasis and psoriatic arthritis identifies new disease loci.

Liu Y ，Helms C ，Liao W ，Zaba LC ，Duan S ，Gardner J ，Wise C ，Miner A ，Malloy MJ ，Pullinger CR ，Kane JP ，Saccone S ，Worthington J ，Bruce I ，Kwok PY ，Menter A ，Krueger J ，Barton A ，Saccone NL ，Bowcock AM ... -  《PLoS Genetics》