Department of Epidemiology, Biostatistics and Occupational Health, McGill University, Montreal, QC, Canada.
Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, QC, Canada.
Sci Rep. 2018 Jan 9;8(1):220. doi: 10.1038/s41598-017-18385-9.
Performance of a recently developed test for association between multivariate phenotypes and sets of genetic variants (MURAT) is demonstrated using measures of bone mineral density (BMD). By combining individual-level whole genome sequenced data from the UK10K study, and imputed genome-wide genetic data on individuals from the Study of Osteoporotic Fractures (SOF) and the Osteoporotic Fractures in Men Study (MrOS), a data set of 8810 individuals was assembled; tests of association were performed between autosomal gene-sets of genetic variants and BMD measured at lumbar spine and femoral neck. Distributions of p-values obtained from analyses of a single BMD phenotype are compared to those from the multivariate tests, across several region definitions and variant weightings. There is evidence of increased power with the multivariate test, although no new loci for BMD were identified. Among 17 genes highlighted either because there were significant p-values in region-based association tests or because they were in well-known BMD genes, 4 windows in 2 genes as well as 6 single SNPs in one of these genes showed association at genome-wide significant thresholds with the multivariate phenotype test but not with the single-phenotype test, Sequence Kernel Association Test (SKAT).
使用骨密度（BMD）测量值来演示最近开发的用于关联多变量表型和遗传变异组的测试（MURAT）的性能。通过结合来自 UK10K 研究的个体水平全基因组测序数据，以及来自骨质疏松性骨折研究（SOF）和男性骨质疏松性骨折研究（MrOS）的个体全基因组遗传数据的推断，组装了一个包含 8810 个人的数据集；在腰椎和股骨颈处测量的 BMD 与常染色体基因座的遗传变异之间进行了关联测试。在多个区域定义和变异加权条件下，比较了单个性状 BMD 分析中获得的 p 值分布与多元测试中的分布。尽管没有发现新的 BMD 基因座，但多元测试的证据表明存在更高的效能。在因基于区域的关联测试中存在显著的 p 值或因为它们是已知的 BMD 基因而被突出显示的 17 个基因中，有 2 个基因中的 4 个窗口以及这些基因之一中的 6 个单核苷酸多态性在与多变量表型测试但不是与单个性状测试（序列核关联测试 [SKAT]）相关联的全基因组显著阈值下显示出关联。
