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

doi:10.1186/s13072-018-0225-x

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

^*Corresponding author for this work

Research output: Contribution to Journal › Article › Academic › peer-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 language	English
Article number	54
Pages (from-to)	1-14
Number of pages	14
Journal	Epigenetics and Chromatin
Volume	11
DOIs	https://doi.org/10.1186/s13072-018-0225-x
Publication status	Published - 25 Sept 2018

Funding

The research leading to these results has received funding from the European Union Seventh Framework Programme (FP7/2007-2013) under grant agreement 602768, and from BBRMI-NL (NWO 184.021.007), Netherlands Organization for Scientific Research(56-464-14192, 480-04-004), National Institutes of Health (NIH 5R37DA018673–03, R01 MH059160, 1RC2 MH089951-01, 4R37DA018673-06, 1R01 MH087646-01A1), European Research Council (230374-GMI), and the Avera Institute for Human Genetics. We gratefully acknowledge grant NWO 480-15-001/674: Netherlands Twin Registry Repository: researching the interplay between genome and environment.

Funders	Funder number
BBRMI-NL
Avera Institute for Human Genetics
European Commission
Seventh Framework Programme	602768
National Institutes of Health	R01 MH059160
Netherlands Organization for Scientific Research	480-04-004, 56-464-14192, 184.021.007
European Research Council	230374-GMI
National Institute on Drug Abuse	R37DA018673
National Institute of Mental Health	R01MH087646, RC2MH089951

Keywords

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

Cohort Studies

Netherlands Twin Register (NTR)

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10.1186/s13072-018-0225-x

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Cite this

Van Dongen, J., Ehli, E. A., Jansen, R., Van Beijsterveldt, C. E. M., Willemsen, G., Hottenga, J. J., Kallsen, N. A., Peyton, S. A., Breeze, C. E., Kluft, C., Heijmans, B. T., Bartels, M., Davies, G. E., & Boomsma, D. I. (2018). Genome-wide analysis of DNA methylation in buccal cells: A study of monozygotic twins and mQTLs. Epigenetics and Chromatin, 11, 1-14. Article 54. https://doi.org/10.1186/s13072-018-0225-x

@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 = sep,

day = "25",

doi = "10.1186/s13072-018-0225-x",

language = "English",

volume = "11",

pages = "1--14",

journal = "Epigenetics and Chromatin",

issn = "1756-8935",

publisher = "BioMed Central",

}

Van Dongen, J, Ehli, EA, Jansen, R, Van Beijsterveldt, CEM, Willemsen, G, Hottenga, JJ, Kallsen, NA, Peyton, SA, Breeze, CE, Kluft, C, Heijmans, BT, Bartels, M, Davies, GE & Boomsma, DI 2018, 'Genome-wide analysis of DNA methylation in buccal cells: A study of monozygotic twins and mQTLs', Epigenetics and Chromatin, vol. 11, 54, pp. 1-14. https://doi.org/10.1186/s13072-018-0225-x

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

UR - https://www.scopus.com/pages/publications/85054033130

UR - https://www.scopus.com/pages/publications/85054033130#tab=citedBy

U2 - 10.1186/s13072-018-0225-x

DO - 10.1186/s13072-018-0225-x

M3 - Article

C2 - 30253792

AN - SCOPUS:85054033130

SN - 1756-8935

VL - 11

SP - 1

EP - 14

JO - Epigenetics and Chromatin

JF - Epigenetics and Chromatin

M1 - 54

ER -

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

Abstract

Funding

Keywords

Cohort Studies

Access to Document

Persistent URL (handle)

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