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Meta-Analysis
. 2013 Oct 1;22(19):4021-9.
doi: 10.1093/hmg/ddt248. Epub 2013 Jun 4.

A systemic sclerosis and systemic lupus erythematosus pan-meta-GWAS reveals new shared susceptibility loci

Jose-Ezequiel Martin  1 , Shervin Assassi, Lina-Marcela Diaz-Gallo, Jasper C Broen, Carmen P Simeon, Ivan Castellvi, Esther Vicente-Rabaneda, Vicente Fonollosa, Norberto Ortego-Centeno, Miguel A González-Gay, Gerard Espinosa, Patricia Carreira; Spanish Scleroderma Group; SLEGEN consortium; U.S. Scleroderma GWAS group; BIOLUPUS; Mayte Camps, Jose M Sabio, Sandra D'alfonso, Madelon C Vonk, Alexandre E Voskuyl, Annemie J Schuerwegh, Alexander Kreuter, Torsten Witte, Gabriella Riemekasten, Nicolas Hunzelmann, Paolo Airo, Lorenzo Beretta, Raffaella Scorza, Claudio Lunardi, Jacob Van Laar, Meng May Chee, Jane Worthington, Arianne Herrick, Christopher Denton, Carmen Fonseca, Filemon K Tan, Frank Arnett, Xiaodong Zhou, John D Reveille, Olga Gorlova, Bobby P C Koeleman, Timothy R D J Radstake, Timothy Vyse, Maureen D Mayes, Marta E Alarcón-Riquelme, Javier Martin
Collaborators, Affiliations
Meta-Analysis

A systemic sclerosis and systemic lupus erythematosus pan-meta-GWAS reveals new shared susceptibility loci

Jose-Ezequiel Martin et al. Hum Mol Genet. .

Abstract

Systemic sclerosis (SSc) and systemic lupus erythematosus (SLE) are two archetypal systemic autoimmune diseases which have been shown to share multiple genetic susceptibility loci. In order to gain insight into the genetic basis of these diseases, we performed a pan-meta-analysis of two genome-wide association studies (GWASs) together with a replication stage including additional SSc and SLE cohorts. This increased the sample size to a total of 21,109 (6835 cases and 14,274 controls). We selected for replication 19 SNPs from the GWAS data. We were able to validate KIAA0319L (P = 3.31 × 10(-11), OR = 1.49) as novel susceptibility loci for SSc and SLE. Furthermore, we also determined that the previously described SLE susceptibility loci PXK (P = 3.27 × 10(-11), OR = 1.20) and JAZF1 (P = 1.11 × 10(-8), OR = 1.13) are shared with SSc. Supporting these new discoveries, we observed that KIAA0319L was overexpressed in peripheral blood cells of SSc and SLE patients compared with healthy controls. With these, we add three (KIAA0319L, PXK and JAZF1) and one (KIAA0319L) new susceptibility loci for SSc and SLE, respectively, increasing significantly the knowledge of the genetic basis of autoimmunity.

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Figures

Figure 1.
Figure 1.
Workflow diagram showing the overall process followed during the present work.
Figure 2.
Figure 2.
Twin Manhattan plot representing the results of the SSc (left side, blue), SLE (right side, green) and combined GWAS analysis (both sides, grey). Selected loci for replication in independent cohorts are marked in red. *SSc plotting represents either the total disease or any of its considered subphenotypes, i.e. ACA positive, ATA positive, lcSSc and dcSSc. **ICA1 and JAZF1 SNPs were selected according to selection criteria three (see Materials and methods), and not because of reaching the significance threshold in the GWAS stage.
Figure 3.
Figure 3.
GRAIL analysis of all the described susceptibility loci for SSc and/or SLE with P < 5 × 10−4. The release 18 of the human genome and the PubMed text as of 2012 were used for the GRAIL analysis.
See this image and copyright information in PMC

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