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

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 tomore » 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.« less
Authors:
 [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
Publication Date:
Grant/Contract Number:
FG02-97ER25308
Type:
Accepted Manuscript
Journal Name:
Genome Research
Additional Journal Information:
Journal Volume: 25; Journal Issue: 6; Journal ID: ISSN 1088-9051
Publisher:
Cold Spring Harbor Laboratory Press
Research Org:
Stanford Univ., CA (United States)
Sponsoring Org:
USDOE National Nuclear Security Administration (NNSA); National Institutes of Health (NIH); National Science Foundation (NSF)
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES
OSTI Identifier:
1344874