Incorporating linkage information into a common disease/rare variant framework.
Incorporating linkage information into a common disease/rare variant framework.
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DOI：
10.1002/gepi.20654
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发表时间：
2011
影响因子：
2.1
通讯作者：
Suarez BK
中科院分区：
文献类型：
--
作者：
Hinrichs AL;Suarez BK
测序技术的最新发展允许调查常见疾病/罕见变异假说。在遗传分析研讨会17数据集，我们有序列数据的不相关的个人和8个大的扩展家系模拟定量和定性表型。第11组的重点是整合连锁信息，他们考虑了几种不同的方法来使用扩展的谱系来识别致病基因和变异。第一个问题是使用标准的连锁或身份的血统信息，以确定区域含有因果罕见的变异。我们发现，罕见的变异大效应分离通过家系正是连锁分析的范围。对于一种常见疾病，我们预期有许多危险基因座，因此异质性连锁分析或一次分析一个家系可能是有用的。第二个问题是使用系谱数据来识别个体进行测序。如果人们能够识别出连锁区域甚至是风险单倍型的携带者，测序将大大提高效率。事实上，在精心挑选的个体中，仅对2.5%的基因组进行测序就可以检测到52%的风险变异，而这些风险变异是通过大量无关个体的全外显子组测序检测到的。最后，我们发现来自家系的连锁信息可以为病例对照关联检验提供权重。我们还发现，基于谱系的关联测试具有与无关个体的测试相同的分箱变异和变异计数问题。显然，当谱系可用时，它们可以为寻找影响常见疾病的罕见变异提供很大的帮助。
Recent developments in sequencing technology have allowed the investigation of the common disease/rare variant hypothesis. In the Genetic Analysis Workshop 17 data set, we have sequence data on both unrelated individuals and eight large extended pedigrees with simulated quantitative and qualitative phenotypes. Group 11, whose focus was incorporating linkage information, considered several different ways to use the extended pedigrees to identify causal genes and variants. The first issue was the use of standard linkage or identity-by-descent information to identify regions containing causal rare variants. We found that rare variants of large effect segregating through pedigrees were precisely the bailiwick of linkage analysis. For a common disease, we anticipate many risk loci, so a heterogeneity linkage analysis or an analysis of a single pedigree at a time may be useful. The second issue was using pedigree data to identify individuals for sequencing. If one can identify linked regions and even carriers of risk haplotypes, the sequencing will be substantially more efficient. In fact, sequencing only 2.5% of the genome in carefully selected individuals can detect 52% of the risk variants that would be detected through whole-exome sequencing in a large number of unrelated individuals. Finally, we found that linkage information from pedigrees can provide weights for case-control association tests. We also found that pedigree-based association tests have the same issues of binning variants and variant counting as those in tests of unrelated individuals. Clearly, when pedigrees are available, they can provide great assistance in the search for rare variants that influence common disorders.