RT Journal Article
SR Electronic
T1 chromMAGMA: regulatory element-centric interrogation of risk variants
JF Life Science Alliance
JO Life Sci. Alliance
FD Life Science Alliance LLC
SP e202201446
DO 10.26508/lsa.202201446
VO 5
IS 10
A1 Robbin Nameki
A1 Anamay Shetty
A1 Eileen Dareng
A1 Jonathan Tyrer
A1 Xianzhi Lin
A1 The Ovarian Cancer Association Consortium
A1 Paul Pharoah
A1 Rosario I Corona
A1 Siddhartha Kar
A1 Kate Lawrenson
YR 2022
UL https://www.life-science-alliance.org/content/5/10/e202201446.abstract
AB 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.