Interrogating local population structure for fine mapping in genome-wide association studies
Interrogating local population structure for fine mapping in genome-wide association studies
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DOI：
10.1093/bioinformatics/btq560
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发表时间：
2010-12-01
期刊：
影响因子：
5.8
通讯作者：
Zhu, Xiaofeng
中科院分区：
文献类型：
--
作者：
Qin, Huaizhen;Morris, Nathan;Zhu, Xiaofeng
动机：调整种群结构是必要的，以避免复杂疾病易感变异的遗传关联研究中的偏见。由于与迁徙、随机遗传漂移或自然选择相关的个体祖先的变异性，种群结构可能因基因组区域而异。目前纠正人口分层的关联方法通常涉及调整研究对象之间的全球血统。结果：我们建议询问当地人口结构以进行精细定位，通过更好地调整由于当地血统造成的混杂效应来更准确地定位真正的偶然基因。通过对全基因组数据集的广泛模拟，我们表明，当局部种群结构是一个重要的混杂因素时，调整全球祖先可能会导致假阳性。相比之下，调整当地血统可以有效地防止由于当地种群结构造成的假阳性，从而可以改善疾病基因定位的精细定位。我们将局部和全球调整应用于来自三个全基因组关联研究的数据集的分析，其中包括欧洲裔美国人、非裔美国人和尼日利亚人。与尼日利亚人相比，欧洲裔美国人和非洲裔美国人在当地血统上表现出更大的差异性。调整当地血统成功地消除了已知的LCT基因SNP与身高之间的虚假关联，这是由于欧洲裔美国人存在的群体结构。
Motivation: Adjustment for population structure is necessary to avoid bias in genetic association studies of susceptibility variants for complex diseases. Population structure may differ from one genomic region to another due to the variability of individual ancestry associated with migration, random genetic drift or natural selection. Current association methods for correcting population stratification usually involve adjustment of global ancestry between study subjects.Results: We suggest interrogating local population structure for fine mapping to more accurately locate true casual genes by better adjusting the confounding effect due to local ancestry. By extensive simulations on genome-wide datasets, we show that adjusting global ancestry may lead to false positives when local population structure is an important confounding factor. In contrast, adjusting local ancestry can effectively prevent false positives due to local population structure and thus can improve fine mapping for disease gene localization. We applied the local and global adjustments to the analysis of datasets from three genome-wide association studies, including European Americans, African Americans and Nigerians. Both European Americans and African Americans demonstrate greater variability in local ancestry than Nigerians. Adjusting local ancestry successfully eliminated the known spurious association between SNPs in the LCT gene and height due to the population structure existed in European Americans.