Evidence for Polygenic Susceptibility to Multiple Sclerosis-The Shape of Things to Come
Evidence for Polygenic Susceptibility to Multiple Sclerosis-The Shape of Things to Come
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DOI：
10.1016/j.ajhg.2010.02.027
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发表时间：
2010-04-09
影响因子：
9.8
通讯作者：
Haines, Jonathan L.
中科院分区：
文献类型：
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作者：
Bush, William S.;Sawcer, Stephen J.;Haines, Jonathan L.
众所周知，患多发性硬化症的风险在受影响个体的亲属中大幅增加，并且这种增加的大部分是遗传决定的。长期以来，观察到的家族复发风险模式一直表明涉及多种变异，但事实证明很难识别个体风险变异，而且关于易感性的遗传结构也知之甚少。通过使用来自两个独立的全基因组关联研究（GWAS）的数据，我们证明了在数千个单独未能显示统计学显著关联证据的变体中，有相当大一部分在通过多个尚未识别的风险基因座的影响偏离零分布的情况下具有等位基因频率。在我们的发现GWAS集中，12，627个SNP的Cochran-Mantel-Haenszel检验（p < 0.2）的集体效应最佳地解释了我们的独立目标GWAS集中MS风险的3%的方差，由Nagelkerke的伪R估计（2）。该模型具有高度显著性拟合（p = 9.90 E-19）。这些结果在统计学上证明了MS易感性的多基因组成部分，并表明迄今为止确定的风险等位基因仅代表风险变体的冰山一角，可能包括数百个适度的影响和可能数千个非常小的影响。
It is well established that the risk of developing multiple sclerosis is substantially increased in the relatives of affected individuals and that most of this increase is genetically determined. The observed pattern of familial recurrence risk has long suggested that multiple variants are involved, but it has proven difficult to identify individual risk variants and little has been established about the genetic architecture underlying susceptibility. By using data from two independent genome-wide association studies (GWAS), we demonstrate that a substantial proportion of the thousands of variants that individually fail to show statistically significant evidence of association have allele frequencies in cases that are skewed away from the null distribution through the effects of multiple as-yet-unidentified risk loci. The collective effect of 12,627 SNPs with Cochran-Mantel-Haenszel test (p < 0.2) in our discovery GWAS set optimally explains similar to 3% of the variance in MS risk in our independent target GWAS set, estimated by Nagelkerke's pseudo-R(2). This model has a highly significant fit (p = 9.90E-19). These results statistically demonstrate a polygenic component to MS susceptibility and suggest that the risk alleles identified to date represent just the tip of an iceberg of risk variants likely to include hundreds of modest effects and possibly thousands of very small effects.