Vignal Charlotte M, Bansal Aruna T, Balding David J
Department of Epidemiology and Public Health, Imperial College London, UK.
Ann Hum Genet. 2011 Nov;75(6):655-64. doi: 10.1111/j.1469-1809.2011.00670.x. Epub 2011 Sep 1.
Rheumatoid arthritis (RA) is strongly associated with the human leukocyte antigen (HLA) genomic region, most notably with a group of HLA-DRB1 alleles termed the shared epitope (SE). There is also substantial evidence of other risk loci in the HLA region, but refinement has been hampered by extensive linkage disequilibrium (LD). Using genotype imputation, we analysed 6575 RA cases and controls with genotypes at 6180 HLA SNPs; about half the subjects had four-digit DRB1 genotypes. Single-SNP tests revealed hundreds of strong associations across the HLA region, even after adjusting for DRB1. We implemented penalised logistic regression in a multi-SNP association analysis using the double-exponential (DE) penalty term on the regression coefficients and the normal-exponential-gamma (NEG). The penalised approaches identified sparse sets of SNPs that could collectively explain most of the association with RA over the whole HLA region. The HLA-DPB1 SNP rs3117225, was consistently identified in our analyses and was confirmed by results from the North American Rheumatoid Arthritis Consortium study (NARAC). We conclude that SNP selection using penalised regression shows a substantial benefit over single-SNP analyses in identifying risk loci in regions of high LD, and the flexibility of the NEG conveys additional advantages.
类风湿性关节炎（RA）与人类白细胞抗原（HLA）基因组区域密切相关，最显著的是与一组称为共享表位（SE）的HLA - DRB1等位基因相关。在HLA区域也有大量其他风险位点的证据，但由于广泛的连锁不平衡（LD），精细化研究受到了阻碍。我们使用基因型推算方法，分析了6575例RA病例和对照，这些个体具有6180个HLA单核苷酸多态性（SNP）的基因型；约一半的受试者具有四位数的DRB1基因型。单SNP检验揭示了整个HLA区域数百个强关联，即使在对DRB1进行校正之后。我们在多SNP关联分析中实施了惩罚逻辑回归，对回归系数使用双指数（DE）惩罚项和正态 - 指数 - 伽马（NEG）。惩罚方法识别出了稀疏的SNP集合，这些SNP集合可以共同解释整个HLA区域与RA的大部分关联。HLA - DPB1 SNP rs3117225在我们的分析中一直被识别出来，并得到了北美类风湿性关节炎联盟研究（NARAC）结果的证实。我们得出结论，在高LD区域识别风险位点时，使用惩罚回归进行SNP选择比单SNP分析显示出显著优势，并且NEG的灵活性带来了额外的优势。
