Department of Electrical Engineering, Center for Computational Biology and Bioinformatics, Columbia University, 1300 S.W. Mudd, 500 West 120th Street, New York, NY 10027, USA.
Hum Genet. 2011 Feb;129(2):161-76. doi: 10.1007/s00439-010-0908-2. Epub 2010 Nov 14.
The human leukocyte antigen (HLA) class II genes HLA-DRB1, -DQA1 and -DQB1 are the strongest genetic factors for type 1 diabetes (T1D). Additional loci in the major histocompatibility complex (MHC) are difficult to identify due to the region's high gene density and complex linkage disequilibrium (LD). To facilitate the association analysis, two novel algorithms were implemented in this study: one for phasing the multi-allelic HLA genotypes in trio families, and one for partitioning the HLA strata in conditional testing. Screening and replication were performed on two large and independent datasets: the Wellcome Trust Case-Control Consortium (WTCCC) dataset of 2,000 cases and 1,504 controls, and the T1D Genetics Consortium (T1DGC) dataset of 2,300 nuclear families. After imputation, the two datasets have 1,941 common SNPs in the MHC, of which 22 were successfully tested and replicated based on the statistical testing stratifying on the detailed DRB1 and DQB1 genotypes. Further conditional tests using the combined dataset confirmed eight novel SNP associations around 31.3 Mb on chromosome 6 (rs3094663, p = 1.66 × 10(-11) and rs2523619, p = 2.77 × 10(-10) conditional on the DR/DQ genotypes). A subsequent LD analysis established TCF19, POU5F1, CCHCR1 and PSORS1C1 as potential causal genes for the observed association.
人类白细胞抗原（HLA）II 类基因 HLA-DRB1、-DQA1 和 -DQB1 是 1 型糖尿病（T1D）最强的遗传因素。由于该区域基因密度高且连锁不平衡（LD）复杂，主要组织相容性复合体（MHC）中的其他基因座难以确定。为了便于关联分析，本研究中实施了两种新算法：一种用于对三核苷酸家族中的多等位 HLA 基因型进行相位分析，另一种用于对条件测试中的 HLA 层进行分区。在两个大型且独立的数据集上进行了筛选和复制：英国 Wellcome 信托基金会病例对照联合会（WTCCC）的 2000 例病例和 1504 例对照的数据集，以及 T1D 遗传学联合会（T1DGC）的 2300 个核家族的数据集。在进行了基因型推断后，两个数据集在 MHC 中有 1941 个共同的 SNP，其中有 22 个 SNP 根据详细的 DRB1 和 DQB1 基因型进行统计测试分层，成功进行了测试和复制。使用合并数据集进一步进行条件测试，在染色体 6 上 31.3 Mb 附近证实了八个新的 SNP 关联（rs3094663，p=1.66×10(-11)和 rs2523619，p=2.77×10(-10)，条件是 DR/DQ 基因型）。随后的 LD 分析确定 TCF19、POU5F1、CCHCR1 和 PSORS1C1 为观察到的关联的潜在因果基因。
