PT  - JOURNAL ARTICLE
AU  - Nameki, Robbin
AU  - Shetty, Anamay
AU  - Dareng, Eileen
AU  - Tyrer, Jonathan
AU  - Lin, Xianzhi
AU - The Ovarian Cancer Association Consortium
AU  - Pharoah, Paul
AU  - Corona, Rosario I
AU  - Kar, Siddhartha
AU  - Lawrenson, Kate
TI  - chromMAGMA: regulatory element-centric interrogation of risk variants
AID  - 10.26508/lsa.202201446
DP  - 2022 Oct 01
TA  - Life Science Alliance
PG  - e202201446
VI  - 5
IP  - 10
4099  - http://www.life-science-alliance.org/content/5/10/e202201446.short
4100  - http://www.life-science-alliance.org/content/5/10/e202201446.full
SO  - Life Sci. Alliance2022 Oct 01; 5
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.