Abstract
Linkage disequilibrium (LD) is a fundamental concept in genetics; critical for studying genetic associations and molecular evolution. However, LD measurements are only reliable for common genetic variants, leaving low-frequency variants unanalyzed. In this work, we introduce cumulative LD (cLD), a stable statistic that captures the rare-variant LD between genetic regions, which reflects more biological interactions between variants, in addition to lack of recombination. We derived the theoretical variance of cLD using delta methods to demonstrate its higher stability than LD for rare variants. This property is also verified by bootstrapped simulations using real data. In application, we find cLD reveals an increased genetic association between genes in 3D chromatin interactions, a phenomenon recently reported negatively by calculating standard LD between common variants. Additionally, we show that cLD is higher between gene pairs reported in interaction databases, identifies unreported protein-protein interactions, and reveals interacting genes distinguishing case/control samples in association studies.
Funder
NSERC discovery grant
NSERC RTI
New Frontiers in Research Fund
University of Calgary VPR Catalyst grant
NSERC Discovery Grant
The National Institutes of Health
American Diabetes Association
Alberta Graduate Excellence Scholarship
Alberta Innovates Graduate Scholarship
Eyes High International Scholarship
CSC Scholarship
Canada Foundation for Innovation
Publisher
Public Library of Science (PLoS)
Subject
Cancer Research,Genetics (clinical),Genetics,Molecular Biology,Ecology, Evolution, Behavior and Systematics