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. 2016 Jan;68(1):174-83.
doi: 10.1002/art.39403.

Identification of a New Susceptibility Locus for Systemic Lupus Erythematosus on Chromosome 12 in Individuals of European Ancestry

F Yesim Demirci  1 , Xingbin Wang  1 , Jennifer A Kelly  2 , David L Morris  3 , M Michael Barmada  1 , Eleanor Feingold  1 , Amy H Kao  4 , Kathy L Sivils  2 , Sasha Bernatsky  5 , Christian Pineau  5 , Ann E Clarke  6 , Rosalind Ramsey-Goldman  7 , Timothy J Vyse  3 , Patrick M Gaffney  2 , Susan Manzi  4 , M Ilyas Kamboh  1
Affiliations

Identification of a New Susceptibility Locus for Systemic Lupus Erythematosus on Chromosome 12 in Individuals of European Ancestry

F Yesim Demirci et al. Arthritis Rheumatol. 2016 Jan.

Abstract

Objective: Genome-wide association studies (GWAS) in individuals of European ancestry identified a number of systemic lupus erythematosus (SLE) susceptibility loci using earlier versions of high-density genotyping platforms. Followup studies on suggestive GWAS regions using larger samples and more markers identified additional SLE loci in subjects of European descent. This multistage study was undertaken to identify novel SLE loci.

Methods: In stage 1, we conducted a new GWAS of SLE in a North American case-control sample of subjects of European ancestry (n = 1,166) genotyped on Affymetrix Genome-Wide Human SNP Array 6.0. In stage 2, we further investigated top new suggestive GWAS hits by in silico evaluation and meta-analysis using an additional data set of subjects of European descent (>2,500 individuals), followed by replication of top meta-analysis findings in another data set of subjects of European descent (>10,000 individuals) in stage 3.

Results: As expected, our GWAS revealed the most significant associations at the major histocompatibility complex locus (6p21), which easily surpassed the genome-wide significance threshold (P < 5 × 10(-8)). Several other SLE signals/loci previously implicated in Caucasians and/or Asians were also confirmed in the stage 1 discovery sample, and the strongest signals were observed at 2q32/STAT4 (P = 3.6 × 10(-7)) and at 8p23/BLK (P = 8.1 × 10(-6)). Stage 2 meta-analyses identified a new genome-wide significant SLE locus at 12q12 (meta P = 3.1 × 10(-8)), which was replicated in stage 3.

Conclusion: Our multistage study identified and replicated a new SLE locus that warrants further followup in additional studies. Publicly available databases suggest that this newly identified SLE signal falls within a functionally relevant genomic region and near biologically important genes.

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Conflict of interest statement

CONFLICT OF INTEREST STATEMENT: The authors have no conflict of interest to disclose.

Figures

Figure 1
Figure 1. Regional association plot on chromosome 12q12 (top panel) and the region overview of the corresponding chromosome segment in Ensembl genome browser (bottom panel)
TOP PANEL: The associations observed in Stage 1 discovery sample are depicted as dark blue diamonds while the results from the meta-analysis of Stage 1 and Stage 2 samples are shown as red dots. The genes located in the region (based on the UCSC genome browser) and the recombination rates by position (light blue line) are also shown. The most relevant SNP with best meta P is labeled. BOTTOM PANEL: The red rectangle shows the large/long intergenic non-coding RNA (lincRNA) genes that reside adjacent to the SLE association signal in this region.
Figure 2
Figure 2. The extent of pairwise LD between the SNPs of interest at the 12q12 locus
The LD plot shows the pairwise r2×100 values between the SNPs of interest in Stage 1 discovery sample.
See this image and copyright information in PMC

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