一种有效的复杂疾病基因定位的检测法(英文)

A Powerful Linkage Disequilibrium Test to Map Loci Underlying Complex Diseases

连锁不平衡 (LD)应用于某些复杂疾病基因的定位 .近年来发展了许多LD定位方法 .除TDT外 ,大多数LD定位方法须先假定无人群混和 .人群混合可增大在疾病基因定位时犯I类错误的机率 ,产生无效结果 .此方法利用LD来检测标记位点和疾病敏感位点 (DSL)的连锁 (有连锁不平衡 )和相关 (有连锁 ) .分析时采用不相关样本 ,已知其父母基因型和至少父母之一为杂合子 ,再将随机样本依基因型不同分类 ,然后对来自不同类的数据应用有力的统计方法进行单独和联合分析 .此LD定位法不仅适用于患病和正常个体 ,而且有效消除据父母基因型分类的样本定位时人群混合的影响 .分析结果和模拟结果也表明此方法解决了在检测标记位点和疾病敏感位点之间的连锁和相关时人群混和的问题 .但与TDT比 ,此法在检测的位点为DSL时更能有效和充分地利用矫正数据 .检测位点不是DSL时 ,此法和TDT法可相互补充更有效地检测连锁的DSL .

Linkage disequilibrium (LD) has been employed to help in the identification of genes underlying some complex diseases. Various LD mapping methods have been under extensive development recently. However,except for the transmission disequilibrium test (TDT),most LD mapping methods explicitly/implicitly assume absence of population admixture. Population admixture may seriously elevate type I error rate for identification of disease genes,rendering the results not robust. Utilizing LD,we develop an approach to test for linkage (in the presence of LD,i.e.,association) and association (in the presence of linkage) between marker and disease susceptibility loci (DSL). Our analyses are performed in unrelated samples whose parental genotype information is known and at least one parent is a heterozygote.Our approach can employ both cases and controls. Random samples are grouped according to the parental genotypes. Data from different groups can be analyzed individually or combined for analyses with higher population admixture on our LD mapping approach. Our analytical results(validated by simulations) and simulation results show that our approach is immune from the problem of population admixture and tests for both linkage and/or association between marker and DSL,similar to the TDT. However, compared with the TDT, our approach can efficiently use data from controls and is generally more powerful,particularly when the locus under test is a DSL. When the locus unde test is not a DSL,the TDT and our approaches may complement each other to ensure tests of higher power to detect a linked DSL,as their relative power varies in different situations.