1] John P. Hussman Institute for Human Genomics, University of Miami, Miller School of Medicine, Miami, Florida, USA. [2].
Nat Genet. 2013 Nov;45(11):1353-60. doi: 10.1038/ng.2770. Epub 2013 Sep 29.
Using the ImmunoChip custom genotyping array, we analyzed 14,498 subjects with multiple sclerosis and 24,091 healthy controls for 161,311 autosomal variants and identified 135 potentially associated regions (P < 1.0 × 10(-4)). In a replication phase, we combined these data with previous genome-wide association study (GWAS) data from an independent 14,802 subjects with multiple sclerosis and 26,703 healthy controls. In these 80,094 individuals of European ancestry, we identified 48 new susceptibility variants (P < 5.0 × 10(-8)), 3 of which we found after conditioning on previously identified variants. Thus, there are now 110 established multiple sclerosis risk variants at 103 discrete loci outside of the major histocompatibility complex. With high-resolution Bayesian fine mapping, we identified five regions where one variant accounted for more than 50% of the posterior probability of association. This study enhances the catalog of multiple sclerosis risk variants and illustrates the value of fine mapping in the resolution of GWAS signals.
我们使用 ImmunoChip 定制基因分型阵列，对 14498 名多发性硬化症患者和 24091 名健康对照者的 161311 个常染色体变体进行了分析，并确定了 135 个潜在相关区域（P < 1.0×10(-4)）。在复制阶段，我们将这些数据与先前独立的 14802 名多发性硬化症患者和 26703 名健康对照者的全基因组关联研究（GWAS）数据相结合。在这些 80094 名欧洲血统个体中，我们确定了 48 个新的易感性变异体（P < 5.0×10(-8)），其中 3 个是在对先前确定的变异体进行条件化后发现的。因此，现在有 110 个已确定的多发性硬化症风险变异体位于主要组织相容性复合体之外的 103 个离散位点。通过高分辨率贝叶斯精细映射，我们确定了五个区域，其中一个变异体占关联后验概率的 50%以上。本研究增强了多发性硬化症风险变异体的目录，并说明了精细映射在解决 GWAS 信号方面的价值。
