Random field modeling of multi-trait multi-locus association for detecting methylation quantitative trait loci

TY - JOUR

T1 - Random field modeling of multi-trait multi-locus association for detecting methylation quantitative trait loci

AU - Lyu, Chen

AU - Huang, Manyan

AU - Liu, Nianjun

AU - Chen, Zhongxue

AU - Lupo, Philip J.

AU - Tycko, Benjamin

AU - Witte, John S.

AU - Hobbs, Charlotte A.

AU - Li, Ming

N1 - Publisher Copyright: © 2022 The Author(s). Published by Oxford University Press. All rights reserved.

PY - 2022/8/15

Y1 - 2022/8/15

N2 - Motivation: CpG sites within the same genomic region often share similar methylation patterns and tend to be co-regulated by multiple genetic variants that may interact with one another. Results: We propose a multi-trait methylation random field (multi-MRF) method to evaluate the joint association between a set of CpG sites and a set of genetic variants. The proposed method has several advantages. First, it is a multi-trait method that allows flexible correlation structures between neighboring CpG sites (e.g. distance-based correlation). Second, it is also a multi-locus method that integrates the effect of multiple common and rare genetic variants. Third, it models the methylation traits with a beta distribution to characterize their bimodal and interval properties. Through simulations, we demonstrated that the proposed method had improved power over some existing methods under various disease scenarios. We further illustrated the proposed method via an application to a study of congenital heart defects (CHDs) with 83 cardiac tissue samples. Our results suggested that gene BACE2, a methylation quantitative trait locus (QTL) candidate, colocalized with expression QTLs in artery tibial and harbored genetic variants with nominal significant associations in two genome-wide association studies of CHD.

AB - Motivation: CpG sites within the same genomic region often share similar methylation patterns and tend to be co-regulated by multiple genetic variants that may interact with one another. Results: We propose a multi-trait methylation random field (multi-MRF) method to evaluate the joint association between a set of CpG sites and a set of genetic variants. The proposed method has several advantages. First, it is a multi-trait method that allows flexible correlation structures between neighboring CpG sites (e.g. distance-based correlation). Second, it is also a multi-locus method that integrates the effect of multiple common and rare genetic variants. Third, it models the methylation traits with a beta distribution to characterize their bimodal and interval properties. Through simulations, we demonstrated that the proposed method had improved power over some existing methods under various disease scenarios. We further illustrated the proposed method via an application to a study of congenital heart defects (CHDs) with 83 cardiac tissue samples. Our results suggested that gene BACE2, a methylation quantitative trait locus (QTL) candidate, colocalized with expression QTLs in artery tibial and harbored genetic variants with nominal significant associations in two genome-wide association studies of CHD.

UR - https://www.scopus.com/pages/publications/85136539058

U2 - 10.1093/bioinformatics/btac443

DO - 10.1093/bioinformatics/btac443

M3 - Article

C2 - 35781319

SN - 1367-4803

VL - 38

SP - 3853

EP - 3862

JO - Bioinformatics

JF - Bioinformatics

IS - 16

ER -