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Title: A pooling-based approach to mapping genetic variants associated with DNA methylation

Journal Article · · Genome Research
 [1];  [2];  [2];  [3];  [3];  [4]
  1. Stanford Univ., CA (United States). Dept. of Computer Science and Dept. of Biology
  2. Univ. of British Columbia, Vancouver, BC (Canada). Centre for Molecular Medicine and Therapeutics and Child and Family Research Inst.
  3. Univ. of British Columbia, Vancouver, BC (Canada). Centre for Molecular Medicine and Therapeutics and Child and Family Research Inst. and Dept. of Medical Genetics
  4. Stanford Univ., CA (United States). Dept. of Biology

DNA methylation is an epigenetic modification that plays a key role in gene regulation. Previous studies have investigated its genetic basis by mapping genetic variants that are associated with DNA methylation at specific sites, but these have been limited to microarrays that cover <2% of the genome and cannot account for allele-specific methylation (ASM). Other studies have performed whole-genome bisulfite sequencing on a few individuals, but these lack statistical power to identify variants associated with DNA methylation. We present a novel approach in which bisulfite-treated DNA from many individuals is sequenced together in a single pool, resulting in a truly genome-wide map of DNA methylation. Compared to methods that do not account for ASM, our approach increases statistical power to detect associations while sharply reducing cost, effort, and experimental variability. As a proof of concept, we generated deep sequencing data from a pool of 60 human cell lines; we evaluated almost twice as many CpGs as the largest microarray studies and identified more than 2000 genetic variants associated with DNA methylation. Here we found that these variants are highly enriched for associations with chromatin accessibility and CTCF binding but are less likely to be associated with traits indirectly linked to DNA, such as gene expression and disease phenotypes. In summary, our approach allows genome-wide mapping of genetic variants associated with DNA methylation in any tissue of any species, without the need for individual-level genotype or methylation data.

Research Organization:
Stanford Univ., CA (United States)
Sponsoring Organization:
USDOE National Nuclear Security Administration (NNSA); National Institutes of Health (NIH); National Science Foundation (NSF)
Grant/Contract Number:
FG02-97ER25308
OSTI ID:
1344874
Journal Information:
Genome Research, Vol. 25, Issue 6; ISSN 1088-9051
Publisher:
Cold Spring Harbor Laboratory PressCopyright Statement
Country of Publication:
United States
Language:
English
Citation Metrics:
Cited by: 19 works
Citation information provided by
Web of Science

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Cited By (16)

Predicting the impact of non-coding variants on DNA methylation journal December 2016
Fine-mapping cis -regulatory variants in diverse human populations posted_content August 2018
IMAGE: High-powered detection of genetic effects on DNA methylation using integrated methylation QTL mapping and allele-specific analysis posted_content September 2019
DeepCpG: accurate prediction of single-cell DNA methylation states using deep learning journal April 2017
Predicting the impact of non-coding variants on DNA methylation journal March 2017
IMAGE: high-powered detection of genetic effects on DNA methylation using integrated methylation QTL mapping and allele-specific analysis journal October 2019
Systematic identification of genetic influences on methylation across the human life course journal March 2016
Methylation of the genes ROD1, NLRC5, and HKR1 is associated with aging in Hainan centenarians journal February 2018
Whole-genome bisulfite sequencing of cell-free DNA identifies signature associated with metastatic breast cancer journal September 2015
Whole-genome bisulfite sequencing with improved accuracy and cost journal August 2018
Molecular mechanisms of coronary disease revealed using quantitative trait loci for TCF21 binding, chromatin accessibility, and chromosomal looping journal June 2020
Fine-mapping cis-regulatory variants in diverse human populations journal January 2019
Regions of common inter-individual DNA methylation differences in human monocytes: genetic basis and potential function journal July 2017
Exploring DNA variant segregation types in pooled genome sequencing enables effective mapping of weeping trait in Malus journal January 2018
DeepCpG: accurate prediction of single-cell DNA methylation states using deep learning. journalarticle January 2017
DNA Methylation in Ovarian Cancer Susceptibility journal December 2020

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