Developing Stats Methods to Detect Rare Genetics Variants in Human Pedigrees

下一代测序技术与高效的DNA捕获方法相结合，为研究复杂表型的遗传基础提供了外显子组测序方法。与全基因组关联研究（GWAS）不同，GWAS只能发现人群中常见的DNA变异（大于1%），外显子组测序对于今天可能对寻找罕见突变感兴趣的科学家来说是一个很好的选择。此外，外显子组测序具有全面测试编码变异的作用的优势，无论是常见的还是罕见的。预计每个基因都可能有功能相关的变异。

Next-generation sequencing technologies coupled with the efficient DNA capture methods provide exome sequencing approach to investigate the genetic basis of complex phenotypes. Unlike whole genome association studies (GWAS) which can only discover variation in DNA that is frequent in the population (great than 1%), exome sequencing is a great choice for scientists today who might be interested in looking for rare mutations. Furthermore, exome sequencing has the advantage of testing comprehensively the role of coding variation, both common and rare. It is anticipated that every gene may harbor functionally relevant variants. Recently, a number of statistical methods become available for analyzing the contribution of rare variants to the development of complex traits. These methods include Combined Multivariate and Collapsing (CMC) Method, Multivariate test of collapsed sub-groups Hotelling T2 test, MANOVA, Fishers product method, Weighted Sum Method and Kernel-based adaptive test. While the merits of these methods have been evaluated extensively for population-based association studies, none of these methods in their current form can be used to analyze the pedigree based association analysis using exome sequencing data. We will develop pedigree-based rare variants analysis approach by treating each affected relatives as dependent pairs and the dependency will be accounted for using correlation matrix. Under the null hypothesis of no association of a set of rare variants with the diseases, the new statistic we have developed is asymptotically distributed as a central distribution. Further, we will use the estimated IBD based weights to account for the dependency of the related affected or unaffected pairs generated from same pedigrees. This method will be used to analyze approximately bipolar disorder pedigrees with exome data. Simulation studies will be used for determining power and type I errors. This method will be used to analyze approximately 100 bipolar disorder pedigrees with exome data as well as data sets with other mental disorders in the future.