Liao Shun-Yao, Tan Yuan-De
Institute of Gerontology, Center for Genetics, Sichuan Academy & Sichuan Provincial People Hospital, University of Electronic Science and Technology of China, Chendu, Sichuan, China.
Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA, United States.
Front Genet. 2024 Jan 16;14:1295327. doi: 10.3389/fgene.2023.1295327. eCollection 2023.
Haplotype-based association analysis has several advantages over single-SNP association analysis. However, to date all haplotype-disease associations have not excluded recombination interference among multiple loci and hence some results might be confounded by recombination interference. Association of sister haplotypes with a complex disease, based on recombination disequilibrium (RD) was presented. Sister haplotypes can be determined by translating notation of DNA base haplotypes to notation of genetic genotypes. Sister haplotypes provide haplotype pairs available for haplotype-disease association analysis. After performing RD tests in control and case cohorts, a two-by-two contingency table can be constructed using sister haplotype pair and case-control pair. With this standard two-by-two table, one can perform classical Chi-square test to find statistical haplotype-disease association. Applying this method to a haplotype dataset of Alzheimer disease (AD), association of sister haplotypes containing ApoE3/4 with risk for AD was identified under no RD. Haplotypes within gene IL-13 were not associated with risk for breast cancer in the case of no RD and no association of haplotypes in gene IL-17A with risk for coronary artery disease were detected without RD. The previously reported associations of haplotypes within these genes with risk for these diseases might be due to strong RD and/or inappropriate haplotype pairs.
基于单倍型的关联分析相对于单核苷酸多态性（SNP）关联分析具有多个优势。然而，迄今为止，所有单倍型与疾病的关联分析都未排除多个基因座间的重组干扰，因此一些结果可能会受到重组干扰的混淆。本文提出了基于连锁不平衡（LD）的姐妹单倍型与复杂疾病的关联分析方法。姐妹单倍型可通过将DNA碱基单倍型的表示法转换为基因基因型的表示法来确定。姐妹单倍型为单倍型与疾病的关联分析提供了可用的单倍型对。在对照组和病例组中进行LD检验后，可使用姐妹单倍型对和病例对照对构建一个2×2列联表。利用这个标准的2×2列联表，可以进行经典的卡方检验来发现单倍型与疾病的统计学关联。将该方法应用于阿尔茨海默病（AD）的单倍型数据集，发现在无LD的情况下，含有载脂蛋白E3/4的姐妹单倍型与AD风险相关。在无LD的情况下，白细胞介素-13（IL-13）基因内的单倍型与乳腺癌风险无关，且在无LD的情况下未检测到白细胞介素-17A（IL-17A）基因内的单倍型与冠状动脉疾病风险的关联。先前报道的这些基因内单倍型与这些疾病风险的关联可能是由于强LD和/或不适当的单倍型对所致。
