Genome-Wide Association Studies and the Problem of Relatedness Among Advanced Intercross Lines and Other Highly Recombinant Populations
Genome-Wide Association Studies and the Problem of Relatedness Among Advanced Intercross Lines and Other Highly Recombinant Populations
复制标题
DOI：
10.1534/genetics.110.116863
复制
发表时间：
2010-07-01
期刊：
影响因子：
3.3
通讯作者：
Palmer, Abraham A.
中科院分区：
文献类型：
--
作者：
Cheng, Riyan;Lim, Jackie E.;Palmer, Abraham A.
模式生物为复杂性状的遗传分析提供了许多优势。然而，特定基因的鉴定常常由于近交系祖先的基因组之间缺乏重组而受到阻碍。最近，人类全基因组关联研究（GWAS）提供了基因水平的映射解决方案，这是可能的，因为大量的积累重组之间不相关的人类受试者。为了在小鼠中获得类似的定位分辨率的改进，我们使用了来自两个近交系（SM/J和LG/J）的第34代高级互交系（AIL）。我们使用模拟来表明，在分析这些数据时，必须考虑受试者之间的家族关系;然后，我们使用了一个混合模型，其中包括多基因效应，以解决我们自己的分析中的这个问题。使用来自相同近交系祖细胞的F-2和AIL小鼠的组合，我们鉴定了与甲基苯丙胺敏感性相关的全基因组显著的亚厘摩位点。例如，在一个实施例中，染色体18; LOD = 10.5）和非药物诱导的运动活性（e.例如，在一个实施例中，8号染色体; LOD = 18.9）。前一个位点的2-LOD支持区间不包含已知基因，而后者仅包含一个基因（Csmd 1）。这种方法是广泛适用的表型和模式生物，并允许GWAS进行多代杂交和近交系之间的家族关系往往是不可避免的。
Model organisms offer many advantages for the genetic analysis of complex traits. However, identification of specific genes is often hampered by a lack of recombination between the genomes of inbred progenitors. Recently, genome-wide association studies (GWAS) in humans have offered gene-level mapping resolution that is possible because of the large number of accumulated recombinations among unrelated human subjects. To obtain analogous improvements in mapping resolution in mice, we used a 34th generation advanced intercross line (AIL) derived from two inbred strains (SM/J and LG/J). We used simulations to show that familial relationships among subjects must be accounted for when analyzing these data; we then used a mixed model that included polygenic effects to address this problem in our own analysis. Using a combination of F-2 and AIL mice derived from the same inbred progenitors, we identified genome-wide significant, subcentimorgan loci that were associated with methamphetamine sensitivity, (e. g., chromosome 18; LOD = 10.5) and non-drug-induced locomotor activity (e. g., chromosome 8; LOD = 18.9). The 2-LOD support interval for the former locus contains no known genes while the latter contains only one gene (Csmd1). This approach is broadly applicable in terms of phenotypes and model organisms and allows GWAS to be performed in multigenerational crosses between and among inbred strains where familial relatedness is often unavoidable.