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chromMAGMA: regulatory element-centric interrogation of risk variants.

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Dareng, Eileen 
Lin, Xianzhi 


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.



Chromatin, Female, Genome-Wide Association Study, Genomics, Humans, Ovary, Regulatory Sequences, Nucleic Acid

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Life Sci Alliance

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Life Science Alliance, LLC
Cancer Research Uk (None)
National Institutes of Health (NIH) (via Cedars-Sinai Medical Center) (sub award 0001331845)
National Institutes of Health (NIH) (via University of Virginia) (GB10524.157581)
National Institutes of Health (NIH) (55376-Cambridge)