chromMAGMA: regulatory element-centric interrogation of risk variants

Abstract

Candidate causal risk variants from genome-wide association studies reside almost exclusively in noncoding regions of the genome and innovative approaches are necessary to understand their biological function. Multi-marker analysis of genomic annotation (MAGMA) is a widely used program that nominates candidate risk genes by mapping single-nucleotide polymorphism summary statistics from genome-wide association studies to gene bodies. We augmented MAGMA to create chromatin-MAGMA (chromMAGMA), a method to nominate candidate risk genes based on the presence of risk variants within noncoding regulatory elements (REs). We applied chromMAGMA to a genetic susceptibility dataset for epithelial ovarian cancer (EOC), a rare gynecologic malignancy characterized by high mortality. This identified 155 unique candidate EOC risk genes across five EOC histotypes; 83% (105/127) of high-grade serous ovarian cancer risk genes had not previously been implicated in this EOC histotype. Risk genes nominated by chromMAGMA converged on mRNA splicing and transcriptional dysregulation pathways. chromMAGMA is a pipeline that nominates candidate risk genes through a gene regulation-focused approach and helps interpret the biological mechanism of noncoding risk variants for complex diseases.

Molecular Management of High-Grade Serous Ovarian Carcinoma

“…A study combining breast and ovarian cancer GWAS datasets and transcriptomic data reported 11 candidate susceptibility genes, including CCNE1, CPNE1, HEATR3, and STRCP1 [169]. Novel analyses integrating candidate genes and gene regulation have encountered additional genes linked to an increased risk of HGSOC [200]. These data emphasize the importance of genome elements in non-coding regions, even though the precise mechanisms underlying these associations remain unclear.…”