Genome-wide analysis of DNA methylation in buccal cells: A study of monozygotic twins and mQTLs

Jenny Van Dongen, Erik A. Ehli, Rick Jansen, Catharina E.M. Van Beijsterveldt, Gonneke Willemsen, Jouke J. Hottenga, Noah A. Kallsen, Shanna A. Peyton, Charles E. Breeze, Cornelis Kluft, Bastiaan T. Heijmans, Meike Bartels, Gareth E. Davies, Dorret I. Boomsma

Research output: Contribution to JournalArticleAcademicpeer-review

Abstract

Background: DNA methylation arrays are widely used in epigenome-wide association studies and methylation quantitative trait locus (mQTL) studies. Here, we performed the first genome-wide analysis of monozygotic (MZ) twin correlations and mQTLs on data obtained with the Illumina MethylationEPIC BeadChip (EPIC array) and compared the performance of the EPIC array to the Illumina HumanMethylation450 BeadChip (HM450 array) for buccal-derived DNA. Results: Good-quality EPIC data were obtained for 102 buccal-derived DNA samples from 49 MZ twin pairs (mean age = 7.5 years, range = 1-10). Differences between MZ twins in the cellular content of buccal swabs were a major driver for differences in their DNA methylation profiles, highlighting the importance to adjust for cellular composition in DNA methylation studies of buccal-derived DNA. After adjusting for cellular composition, the genome-wide mean correlation (r) between MZ twins was 0.21 for the EPIC array, and cis mQTL analysis in 84 twins identified 1,296,323 significant associations (FDR 5%), encompassing 33,749 methylation sites and 616,029 genetic variants. MZ twin correlations were slightly larger (p < 2.2 × 10-16) for novel EPIC probes (N = 383,066, mean r = 0.22) compared to probes that are also present on HM450 (N = 406,822, mean r = 0.20). In line with this observation, a larger percentage of novel EPIC probes was associated with genetic variants (novel EPIC probes with significant mQTL 4.7%, HM450 probes with mQTL 3.9%, p < 2.2 × 10-16). Methylation sites with a large MZ correlation and sites associated with mQTLs were most strongly enriched in epithelial cell DNase I hypersensitive sites (DHSs), enhancers, and histone mark H3K4me3. Conclusions: We conclude that the contribution of familial factors to individual differences in DNA methylation and the effect of mQTLs are larger for novel EPIC probes, especially those within regulatory elements connected to active regions specific to the investigated tissue.

Original languageEnglish
Article number54
Pages (from-to)1-14
Number of pages14
JournalEpigenetics and Chromatin
Volume11
DOIs
Publication statusPublished - 25 Sep 2018

Fingerprint

Monozygotic Twins
Cheek
DNA Methylation
Methylation
Quantitative Trait Loci
Genome
DNA
Histone Code
Deoxyribonuclease I
Oligonucleotide Array Sequence Analysis
Individuality
Epithelial Cells

Keywords

  • 450 k
  • Array
  • Buccal
  • Children
  • DNA methylation
  • EPIC
  • Epigenetics
  • Illumina
  • QTL
  • Twin study

Cite this

@article{eae44eb2c465485685c7ef3dd30fd719,
title = "Genome-wide analysis of DNA methylation in buccal cells: A study of monozygotic twins and mQTLs",
abstract = "Background: DNA methylation arrays are widely used in epigenome-wide association studies and methylation quantitative trait locus (mQTL) studies. Here, we performed the first genome-wide analysis of monozygotic (MZ) twin correlations and mQTLs on data obtained with the Illumina MethylationEPIC BeadChip (EPIC array) and compared the performance of the EPIC array to the Illumina HumanMethylation450 BeadChip (HM450 array) for buccal-derived DNA. Results: Good-quality EPIC data were obtained for 102 buccal-derived DNA samples from 49 MZ twin pairs (mean age = 7.5 years, range = 1-10). Differences between MZ twins in the cellular content of buccal swabs were a major driver for differences in their DNA methylation profiles, highlighting the importance to adjust for cellular composition in DNA methylation studies of buccal-derived DNA. After adjusting for cellular composition, the genome-wide mean correlation (r) between MZ twins was 0.21 for the EPIC array, and cis mQTL analysis in 84 twins identified 1,296,323 significant associations (FDR 5{\%}), encompassing 33,749 methylation sites and 616,029 genetic variants. MZ twin correlations were slightly larger (p < 2.2 × 10-16) for novel EPIC probes (N = 383,066, mean r = 0.22) compared to probes that are also present on HM450 (N = 406,822, mean r = 0.20). In line with this observation, a larger percentage of novel EPIC probes was associated with genetic variants (novel EPIC probes with significant mQTL 4.7{\%}, HM450 probes with mQTL 3.9{\%}, p < 2.2 × 10-16). Methylation sites with a large MZ correlation and sites associated with mQTLs were most strongly enriched in epithelial cell DNase I hypersensitive sites (DHSs), enhancers, and histone mark H3K4me3. Conclusions: We conclude that the contribution of familial factors to individual differences in DNA methylation and the effect of mQTLs are larger for novel EPIC probes, especially those within regulatory elements connected to active regions specific to the investigated tissue.",
keywords = "450 k, Array, Buccal, Children, DNA methylation, EPIC, Epigenetics, Illumina, QTL, Twin study",
author = "{Van Dongen}, Jenny and Ehli, {Erik A.} and Rick Jansen and {Van Beijsterveldt}, {Catharina E.M.} and Gonneke Willemsen and Hottenga, {Jouke J.} and Kallsen, {Noah A.} and Peyton, {Shanna A.} and Breeze, {Charles E.} and Cornelis Kluft and Heijmans, {Bastiaan T.} and Meike Bartels and Davies, {Gareth E.} and Boomsma, {Dorret I.}",
year = "2018",
month = "9",
day = "25",
doi = "10.1186/s13072-018-0225-x",
language = "English",
volume = "11",
pages = "1--14",
journal = "Epigenetics & Chromatin",
issn = "1756-8935",
publisher = "BioMed Central",

}

Genome-wide analysis of DNA methylation in buccal cells : A study of monozygotic twins and mQTLs. / Van Dongen, Jenny; Ehli, Erik A.; Jansen, Rick; Van Beijsterveldt, Catharina E.M.; Willemsen, Gonneke; Hottenga, Jouke J.; Kallsen, Noah A.; Peyton, Shanna A.; Breeze, Charles E.; Kluft, Cornelis; Heijmans, Bastiaan T.; Bartels, Meike; Davies, Gareth E.; Boomsma, Dorret I.

In: Epigenetics and Chromatin, Vol. 11, 54, 25.09.2018, p. 1-14.

Research output: Contribution to JournalArticleAcademicpeer-review

TY - JOUR

T1 - Genome-wide analysis of DNA methylation in buccal cells

T2 - A study of monozygotic twins and mQTLs

AU - Van Dongen, Jenny

AU - Ehli, Erik A.

AU - Jansen, Rick

AU - Van Beijsterveldt, Catharina E.M.

AU - Willemsen, Gonneke

AU - Hottenga, Jouke J.

AU - Kallsen, Noah A.

AU - Peyton, Shanna A.

AU - Breeze, Charles E.

AU - Kluft, Cornelis

AU - Heijmans, Bastiaan T.

AU - Bartels, Meike

AU - Davies, Gareth E.

AU - Boomsma, Dorret I.

PY - 2018/9/25

Y1 - 2018/9/25

N2 - Background: DNA methylation arrays are widely used in epigenome-wide association studies and methylation quantitative trait locus (mQTL) studies. Here, we performed the first genome-wide analysis of monozygotic (MZ) twin correlations and mQTLs on data obtained with the Illumina MethylationEPIC BeadChip (EPIC array) and compared the performance of the EPIC array to the Illumina HumanMethylation450 BeadChip (HM450 array) for buccal-derived DNA. Results: Good-quality EPIC data were obtained for 102 buccal-derived DNA samples from 49 MZ twin pairs (mean age = 7.5 years, range = 1-10). Differences between MZ twins in the cellular content of buccal swabs were a major driver for differences in their DNA methylation profiles, highlighting the importance to adjust for cellular composition in DNA methylation studies of buccal-derived DNA. After adjusting for cellular composition, the genome-wide mean correlation (r) between MZ twins was 0.21 for the EPIC array, and cis mQTL analysis in 84 twins identified 1,296,323 significant associations (FDR 5%), encompassing 33,749 methylation sites and 616,029 genetic variants. MZ twin correlations were slightly larger (p < 2.2 × 10-16) for novel EPIC probes (N = 383,066, mean r = 0.22) compared to probes that are also present on HM450 (N = 406,822, mean r = 0.20). In line with this observation, a larger percentage of novel EPIC probes was associated with genetic variants (novel EPIC probes with significant mQTL 4.7%, HM450 probes with mQTL 3.9%, p < 2.2 × 10-16). Methylation sites with a large MZ correlation and sites associated with mQTLs were most strongly enriched in epithelial cell DNase I hypersensitive sites (DHSs), enhancers, and histone mark H3K4me3. Conclusions: We conclude that the contribution of familial factors to individual differences in DNA methylation and the effect of mQTLs are larger for novel EPIC probes, especially those within regulatory elements connected to active regions specific to the investigated tissue.

AB - Background: DNA methylation arrays are widely used in epigenome-wide association studies and methylation quantitative trait locus (mQTL) studies. Here, we performed the first genome-wide analysis of monozygotic (MZ) twin correlations and mQTLs on data obtained with the Illumina MethylationEPIC BeadChip (EPIC array) and compared the performance of the EPIC array to the Illumina HumanMethylation450 BeadChip (HM450 array) for buccal-derived DNA. Results: Good-quality EPIC data were obtained for 102 buccal-derived DNA samples from 49 MZ twin pairs (mean age = 7.5 years, range = 1-10). Differences between MZ twins in the cellular content of buccal swabs were a major driver for differences in their DNA methylation profiles, highlighting the importance to adjust for cellular composition in DNA methylation studies of buccal-derived DNA. After adjusting for cellular composition, the genome-wide mean correlation (r) between MZ twins was 0.21 for the EPIC array, and cis mQTL analysis in 84 twins identified 1,296,323 significant associations (FDR 5%), encompassing 33,749 methylation sites and 616,029 genetic variants. MZ twin correlations were slightly larger (p < 2.2 × 10-16) for novel EPIC probes (N = 383,066, mean r = 0.22) compared to probes that are also present on HM450 (N = 406,822, mean r = 0.20). In line with this observation, a larger percentage of novel EPIC probes was associated with genetic variants (novel EPIC probes with significant mQTL 4.7%, HM450 probes with mQTL 3.9%, p < 2.2 × 10-16). Methylation sites with a large MZ correlation and sites associated with mQTLs were most strongly enriched in epithelial cell DNase I hypersensitive sites (DHSs), enhancers, and histone mark H3K4me3. Conclusions: We conclude that the contribution of familial factors to individual differences in DNA methylation and the effect of mQTLs are larger for novel EPIC probes, especially those within regulatory elements connected to active regions specific to the investigated tissue.

KW - 450 k

KW - Array

KW - Buccal

KW - Children

KW - DNA methylation

KW - EPIC

KW - Epigenetics

KW - Illumina

KW - QTL

KW - Twin study

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