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Statistical Methods to Understand the Genetic Architecture of Complex Traits


Genome-wide association studies (GWAS) have successfully identified thousands of risk loci for complex traits.

Identifying these variants requires annotating all possible variations between any two individuals, followed by

detecting the variants that affect the disease status or traits.

High-throughput sequencing (HTS) advancements have made it possible to sequence

cohort of individuals in an efficient manner both in term of cost and time. However, HTS technologies have

raised many computational challenges. I first propose an efficient method to recover dense genotype

data by leveraging low sequencing and imputation techniques. Then,

I introduce a novel statistical method (CNVeM) to identify Copy-number variations (CNVs) loci using HTS data. CNVeM was the

first method that incorporates multi-mapped reads, which are discarded by all existing methods.

Unfortunately, among all GWAS variants only a handful of them have been successfully validated to be biologically causal variants. Identifying causal variants can aid us to understand the biological mechanism of traits or diseases. However, detecting the causal variants is challenging due to linkage disequilibrium (LD) and the fact that some loci contain more than one causal variant. In my thesis, I will introduce CAVIAR (CAusal Variants Identification in Associated Regions) that is a new statistical method for fine mapping. The main advantage of CAVIAR is that we predict a set of variants for each locus that will contain all of the true causal variants with a high confidence level (e.g. 95%) even when the locus contains multiple causal variants. Next, I aim to understand the underlying mechanism of GWAS risk loci. A standard approach to uncover the mechanism of GWAS risk loci is to integrate results of GWAS and expression quantitative trait loci (eQTL) studies; we attempt to identify whether or not a significant GWAS variant also influences expression at a nearby gene in a specific tissue. However, detecting the same variant being causal in both GWAS and eQTL is challenging due to complex LD structure. I will introduce eCAVIAR (eQTL and GWAS CAusal Variants Identification in Associated Regions), a statistical method to compute the probability that the same variant is responsible for both the GWAS and eQTL signal, while accounting for complex LD structure. We integrate Glucose and Insulin-related traits meta-analysis with GTEx to detect the target genes and the most relevant tissues. Interestingly, we observe that most loci do not colocalize between GWAS and eQTL. Lastly, I propose an approach called phenotype imputation that allows one to perform GWAS on a phenotype that is difficult to collect. In our approach, we leverage the correlation structure between multiple phenotypes to impute the uncollected phenotype. I demonstrate that we can analytically calculate the statistical power of association test using imputed phenotype, which can be helpful for study design purposes

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