Integrated analysis of variants and pathways in genome-wide association studies using polygenic models of disease

TL;DR

This paper introduces a sparse regression method that identifies disease-associated pathways and variants in GWAS data, improving detection of small-effect genetic factors in complex diseases like Crohn's disease.

Contribution

The study presents a novel integrated approach combining pathway enrichment estimation with variant prioritization using sparse regression, enhancing GWAS analysis accuracy.

Findings

Enrichment of cytokine signaling pathways in Crohn's disease

Prioritized variants align with previously reported disease associations

Method improves detection of small-effect genetic variants

Abstract

Many common diseases are highly polygenic, modulated by a large number genetic factors with small effects on susceptibility to disease. These small effects are difficult to map reliably in genetic association studies. To address this problem, researchers have developed methods that aggregate information over sets of related genes, such as biological pathways, to identify gene sets that are enriched for genetic variants associated with disease. However, these methods fail to answer a key question: which genes and genetic variants are associated with disease risk? We develop a method based on sparse multiple regression that simultaneously identifies enriched pathways, and prioritizes the variants within these pathways, to locate additional variants associated with disease susceptibility. A central feature of our approach is an estimate of the strength of enrichment, which yields a coherent way to prioritize variants in enriched pathways. We illustrate the benefits of our approach in a genome-wide association study of Crohn's disease with ~440,000 genetic variants genotyped for ~4700 study subjects. We obtain strong support for enrichment of IL-12, IL-23 and other cytokine signaling pathways. Furthermore, prioritizing variants in these enriched pathways yields support for additional disease-association variants, all of which have been independently reported in other case-control studies for Crohn's disease.