Whole genome association study of rheumatoid arthritis using 27 039 microsatellites
Whole genome association study of rheumatoid arthritis using 27 039 microsatellites
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DOI：
10.1093/hmg/ddi234
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发表时间：
2005-08-15
影响因子：
3.5
通讯作者：
Inoko, H
中科院分区：
文献类型：
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作者：
Tamiya, G;Shinya, M;Inoko, H
当前人类全基因组研究的一个主要目标是确定复杂疾病的遗传基础。然而，目前仍然缺乏一种公正、可靠、具有成本效益且全面的方法来分析整个基因组以了解复杂疾病的关联性，或者存在问题。因此，我们为复杂疾病的全基因组关联研究制定了一种实用且有效的策略，通过使用 27 039 个微卫星的集合和 DNA 合并方法在独立病例对照群体的三个连续基因组筛选中以 100 kb 间隔绘制人类基因组图。我们方法的最后一步包括通过单核苷酸多态性 (SNP) 分析对候选易感 DNA 区域进行精细定位。这种方法在类风湿性关节炎的治疗中得到了验证，类风湿性关节炎是一种破坏性关节疾病，影响高达 1% 的人口。总共确定了 47 个候选区域。前七个基因座经受了最严格的统计测试，被分解为四个染色体上的单个基因和/或 SNP，包括先前已知的 6p21.3 编码的主要组织相容性复合体基因 HLA-DRB1。因此，基于微卫星的全基因组关联分析辅以末期 SNP 分型，为包括常见疾病在内的多因素病理学的遗传解析提供了新工具。
A major goal of current human genome-wide studies is to identify the genetic basis of complex disorders. However, the availability of an unbiased, reliable, cost efficient and comprehensive methodology to analyze the entire genome for complex disease association is still largely lacking or problematic. Therefore, we have developed a practical and efficient strategy for whole genome association studies of complex diseases by charting the human genome at 100 kb intervals using a collection of 27 039 microsatellites and the DNA pooling method in three successive genomic screens of independent case-control populations. The final step In our methodology consists of fine mapping of the candidate susceptible DNA regions by single nucleotide polymorphisms (SNPs) analysis. This approach was validated upon application to rheumatoid arthritis, a destructive joint disease affecting up to 1% of the population. A total of 47 candidate regions were identified. The top seven loci, withstanding the most stringent statistical tests, were dissected down to individual genes and/or SNPs on four chromosomes, including the previously known 6p21.3-encoded Major Histocompatibility Complex gene, HLA-DRB1. Hence, microsatellite-based genome-wide association analysis complemented by end stage SNP typing provides a new tool for genetic dissection of multifactorial pathologies including common diseases.