Design and Association Methods for Next-generation Sequencing Studies for Quantitative Traits.

Abstract

Advances in exome sequencing and the development of exome genotyping arrays are enabling explorations of association between rare coding variants and complex traits using sequencing-based GWAS. However, the cost of sequencing remains high, optimal study design for sequencing-based association studies is an open question, powerful association methods and software to detect trait-associated rare and low-frequency variants are in great need. Containing 5% of information in human genome, chromosome X analysis has been largely neglected in routine GWAS analysis. In this dissertation, I focus on three topics: First, I describe a computationally efficient approach to re-construct gene-level association test statistics from single-variant summary statistics and their covariance matrices for single studies and meta-analyses. By simulation and real data examples, I evaluate our methods under the null, investigate scenarios when family samples have larger power than population samples, compare power of different types of gene-level tests under various trait-generating models, and demonstrate the usage of our methods and the C++ software, RAREMETAL, by meta-analyzing SardiNIA and HUNT data on lipids levels. Second, I describe a variance component approach and a series of gene-level tests for X-linked rare variants analysis. By simulations, I demonstrate that our methods are well controlled under the null. I evaluate power to detect an autosomal or X-linked gene of same effect size, and investigate the effect of sex ratio in a sample to power of detecting an X-linked gene. Finally I demonstrate usage of our method and the C++ software by analyzing various quantitative traits measured in the SardiNIA study and report detected X-linked variants and genes. Third, I describe a novel likelihood-based approach and the C++ software, RAREFY, to prioritize samples that are more likely to be carriers of trait-associated variants in a sample, with limited budget. I first describe the statistical method for small pedigrees and then describe an MCMC approach to make our method computationally feasible for large pedigrees. By simulations and real data analysis, I compare our approach with other methods in both trait-associated allele discovery power and association power, and demonstrate the usage of our method on pedigrees from the SardiNIA study.PhDBiostatisticsUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/113521/1/sfengsph_1.pd