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

Abstract:

: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. 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.

journal_name

Genome Res

journal_title

Genome research

authors

Kaplow IM,MacIsaac JL,Mah SM,McEwen LM,Kobor MS,Fraser HB

doi

10.1101/gr.183749.114

subject

Has Abstract

pub_date

2015-06-01 00:00:00

pages

907-17

issue

6

eissn

1088-9051

issn

1549-5469

pii

gr.183749.114

journal_volume

25

pub_type

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