University of Pittsburgh, Pittsburgh, Pennsylvania.
Oklahoma Medical Research Foundation, Oklahoma City.
Arthritis Rheumatol. 2016 Jan;68(1):174-83. doi: 10.1002/art.39403.
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.
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.
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.
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.
全基因组关联研究（GWAS）在欧洲血统个体中使用早期版本的高密度基因分型平台确定了许多系统性红斑狼疮（SLE）易感位点。使用更大的样本量和更多的标记物对提示性 GWAS 区域的后续研究在欧洲血统的受试者中确定了其他 SLE 位点。这项多阶段研究旨在确定新的 SLE 位点。
在第一阶段，我们对欧洲血统的北美病例对照样本（n=1166）进行了 SLE 的新 GWAS，这些样本在 Affymetrix Genome-Wide Human SNP Array 6.0 上进行了基因分型。在第二阶段，我们通过使用具有欧洲血统的受试者的另一个数据集（>2500 人）进行的基于计算机的评估和荟萃分析进一步研究了顶级新的提示性 GWAS 命中，然后在欧洲血统的另一个数据集（>10000 人）中复制了顶级荟萃分析结果在第三阶段。
正如预期的那样，我们的 GWAS 揭示了主要组织相容性复合体（6p21）最显著的关联，这很容易超过全基因组显著性阈值（P<5×10(-8)）。先前在白种人和/或亚洲人中涉及的其他几个 SLE 信号/位点也在第一阶段发现样本中得到了证实，最强的信号出现在 2q32/STAT4（P=3.6×10(-7)）和 8p23/BLK（P=8.1×10(-6)）。第二阶段的荟萃分析确定了一个新的全基因组显著的 SLE 位点 12q12（荟萃 P=3.1×10(-8)），该位点在第三阶段得到了复制。
我们的多阶段研究确定并复制了一个新的 SLE 位点，这在其他研究中值得进一步跟进。公开可用的数据库表明，这个新确定的 SLE 信号落在一个具有功能相关性的基因组区域内，并且靠近生物学上重要的基因。
