Abecasis Gonçalo R, Wigginton Janis E
Center for Statistical Genetics, Department of Biostatistics, University of Michigan, Ann Arbor, MI, 48109, USA.
Am J Hum Genet. 2005 Nov;77(5):754-67. doi: 10.1086/497345. Epub 2005 Sep 20.
Single-nucleotide polymorphisms (SNPs) are rapidly replacing microsatellites as the markers of choice for genetic linkage studies and many other studies of human pedigrees. Here, we describe an efficient approach for modeling linkage disequilibrium (LD) between markers during multipoint analysis of human pedigrees. Using a gene-counting algorithm suitable for pedigree data, our approach enables rapid estimation of allele and haplotype frequencies within clusters of tightly linked markers. In addition, with the use of a hidden Markov model, our approach allows for multipoint pedigree analysis with large numbers of SNP markers organized into clusters of markers in LD. Simulation results show that our approach resolves previously described biases in multipoint linkage analysis with SNPs that are in LD. An updated version of the freely available Merlin software package uses the approach described here to perform many common pedigree analyses, including haplotyping and haplotype frequency estimation, parametric and nonparametric multipoint linkage analysis of discrete traits, variance-components and regression-based analysis of quantitative traits, calculation of identity-by-descent or kinship coefficients, and case selection for follow-up association studies. To illustrate the possibilities, we examine a data set that provides evidence of linkage of psoriasis to chromosome 17.
单核苷酸多态性(SNPs)正迅速取代微卫星,成为遗传连锁研究及许多其他人类家系研究的首选标记。在此,我们描述了一种在人类家系多点分析过程中对标记间连锁不平衡(LD)进行建模的有效方法。利用一种适用于家系数据的基因计数算法,我们的方法能够快速估计紧密连锁标记簇内的等位基因和单倍型频率。此外,通过使用隐马尔可夫模型,我们的方法允许对大量组织成LD标记簇的SNP标记进行多点家系分析。模拟结果表明,我们的方法解决了先前描述的在对处于LD的SNP进行多点连锁分析时的偏差问题。免费可得的Merlin软件包的更新版本采用此处描述的方法来进行许多常见的家系分析,包括单倍型分型和单倍型频率估计、离散性状的参数化和非参数化多点连锁分析、数量性状的方差成分和基于回归的分析、计算同源系数或亲缘系数,以及为后续关联研究选择病例。为说明其可能性,我们研究了一个数据集,该数据集提供了银屑病与17号染色体连锁的证据。