New Approaches to Identify Gene-by-Gene Interactions in Genome Wide Association Studies

TL;DR

This paper introduces a new penalized regression method incorporating biological knowledge to detect gene-gene interactions in GWAS, and extends it to multi-cohort meta-analysis, demonstrating improved performance over existing strategies.

Contribution

It presents a novel network-based penalized regression approach for single-cohort analysis and develops three meta-analysis procedures for multi-cohort GWAS, enhancing detection of gene interactions.

Findings

Simulations show improved detection of gene interactions with biological knowledge.

Splitting cohorts into two groups yields the best meta-analysis results.

Application to Framingham data demonstrates practical utility.

Abstract

Genetic variants identified to date by genome-wide association studies only explain a small fraction of total heritability. Gene-by-gene interaction is one important potential source of unexplained heritability. In the first part of this dissertation, a novel approach to detect such interactions is proposed. This approach utilizes penalized regression and sparse estimation principles, and incorporates outside biological knowledge through a network-based penalty. The method is tested on simulated data under various scenarios. Simulations show that with reasonable outside biological knowledge, the new method performs noticeably better than current stage-wise strategies, especially when the marginal strength of main effects is weak. The proposed method is designed for single-cohort analyses. However, it is generally acknowledged that only multi-cohort analyses have sufficient power to uncover genes and gene-by-gene interactions with moderate effects on traits, such as likely underlie complex diseases. Multi-cohort, meta-analysis approaches for penalized regressions are developed and investigated in the second part of this dissertation. Specifically, I propose two different ways of utilizing data-splitting principles in multi-cohort settings and develop three procedures to conduct meta-analysis. Using the method developed in the first part of this dissertation as an example of penalized regressions, three proposed meta-analysis procedures are compared to mega-analysis using a simulation study. The results suggest that the best approach is to split the participating cohorts into two groups. In the last part of this dissertation, the novel method developed in the first part is applied to the Framingham Heart Study measures on total plasma Immunoglobulin E (IgE) concentrations, C-reactive protein levels, and Fasting Glucose.