Disease variants alter transcription factor levels and methylation of their binding sites

Marc Jan Bonder; René Luijk; Daria V Zhernakova; Matthijs Moed; Patrick Deelen; Martijn Vermaat; Maarten van Iterson; Freerk van Dijk; Michiel van Galen; Jan Bot; Roderick C Slieker; P Mila Jhamai; Michael Verbiest; H Eka D Suchiman; Marijn Verkerk; Ruud van der Breggen; Jeroen van Rooij; Nico Lakenberg; Wibowo Arindrarto; Szymon M Kielbasa; Iris Jonkers; Peter van 't Hof; Irene Nooren; Marian Beekman; Joris Deelen; Diana van Heemst; Alexandra Zhernakova; Ettje F Tigchelaar; Morris a. Swertz; Albert Hofman; André G Uitterlinden; René Pool; J. van Dongen; Jouke J Hottenga; Coen D A Stehouwer; Carla J H van der Kallen; Casper G Schalkwijk; Leonard H van den Berg; Erik W van Zwet; Hailiang Mei; Yang Li; Mathieu Lemire; Thomas J Hudson; P. Eline Slagboom; Cisca Wijmenga; Jan H Veldink; Marleen J. Van Greevenbroek; Cornelia M van Duijn; Dorret I Boomsma; Aaron Isaacs; BIOS Consortium

doi:10.1038/ng.3721

Disease variants alter transcription factor levels and methylation of their binding sites

Marc Jan Bonder, René Luijk, Daria V Zhernakova, Matthijs Moed, Patrick Deelen, Martijn Vermaat, Maarten van Iterson, Freerk van Dijk, Michiel van Galen, Jan Bot, Roderick C Slieker, P Mila Jhamai, Michael Verbiest, H Eka D Suchiman, Marijn Verkerk, Ruud van der Breggen, Jeroen van Rooij, Nico Lakenberg, Wibowo Arindrarto, Szymon M KielbasaIris Jonkers, Peter van 't Hof, Irene Nooren, Marian Beekman, Joris Deelen, Diana van Heemst, Alexandra Zhernakova, Ettje F Tigchelaar, Morris a. Swertz, Albert Hofman, André G Uitterlinden, René Pool, J. van Dongen, Jouke J Hottenga, Coen D A Stehouwer, Carla J H van der Kallen, Casper G Schalkwijk, Leonard H van den Berg, Erik W van Zwet, Hailiang Mei, Yang Li, Mathieu Lemire, Thomas J Hudson, P. Eline Slagboom, Cisca Wijmenga, Jan H Veldink, Marleen J. Van Greevenbroek, Cornelia M van Duijn, Dorret I Boomsma, Aaron Isaacs, BIOS Consortium

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Abstract

Most disease-associated genetic variants are noncoding, making it challenging to design experiments to understand their functional consequences. Identification of expression quantitative trait loci (eQTLs) has been a powerful approach to infer the downstream effects of disease-associated variants, but most of these variants remain unexplained. The analysis of DNA methylation, a key component of the epigenome, offers highly complementary data on the regulatory potential of genomic regions. Here we show that disease-associated variants have widespread effects on DNA methylation in trans that likely reflect differential occupancy of trans binding sites by cis-regulated transcription factors. Using multiple omics data sets from 3,841 Dutch individuals, we identified 1,907 established trait-associated SNPs that affect the methylation levels of 10,141 different CpG sites in trans (false discovery rate (FDR) < 0.05). These included SNPs that affect both the expression of a nearby transcription factor (such as NFKB1, CTCF and NKX2-3) and methylation of its respective binding site across the genome. Trans methylation QTLs effectively expose the downstream effects of disease-associated variants.

Original language	English
Pages (from-to)	131-138
Number of pages	11
Journal	Nature Genetics
Volume	49
Issue number	1
Early online date	5 Dec 2016
DOIs	https://doi.org/10.1038/ng.3721
Publication status	Published - Jan 2017

Funding

Funders	Funder number
BBMRI-NL
Dutch Research Council
Dutch Government
FP7/2007
Seventh Framework Programme	259867
Seventh Framework Programme
European Research Council	637640
European Research Council
Nederlandse Organisatie voor Wetenschappelijk Onderzoek	ZonMW-VIDI 917.14.374, 184.021.007
Nederlandse Organisatie voor Wetenschappelijk Onderzoek

Keywords

Journal Article

Cohort Studies

Netherlands Twin Register (NTR)

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/ng.3721

Disease variants alter transcription factor levels and methylation of their binding sitesFinal published version, 1.77 MBLicence: Article 25fa Dutch Copyright Act

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Bonder, M. J., Luijk, R., Zhernakova, D. V., Moed, M., Deelen, P., Vermaat, M., van Iterson, M., van Dijk, F., van Galen, M., Bot, J., Slieker, R. C., Jhamai, P. M., Verbiest, M., Suchiman, H. E. D., Verkerk, M., van der Breggen, R., van Rooij, J., Lakenberg, N., Arindrarto, W., ... BIOS Consortium (2017). Disease variants alter transcription factor levels and methylation of their binding sites. Nature Genetics, 49(1), 131-138. https://doi.org/10.1038/ng.3721

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abstract = "Most disease-associated genetic variants are noncoding, making it challenging to design experiments to understand their functional consequences. Identification of expression quantitative trait loci (eQTLs) has been a powerful approach to infer the downstream effects of disease-associated variants, but most of these variants remain unexplained. The analysis of DNA methylation, a key component of the epigenome, offers highly complementary data on the regulatory potential of genomic regions. Here we show that disease-associated variants have widespread effects on DNA methylation in trans that likely reflect differential occupancy of trans binding sites by cis-regulated transcription factors. Using multiple omics data sets from 3,841 Dutch individuals, we identified 1,907 established trait-associated SNPs that affect the methylation levels of 10,141 different CpG sites in trans (false discovery rate (FDR) < 0.05). These included SNPs that affect both the expression of a nearby transcription factor (such as NFKB1, CTCF and NKX2-3) and methylation of its respective binding site across the genome. Trans methylation QTLs effectively expose the downstream effects of disease-associated variants.",

keywords = "Journal Article",

author = "Bonder, {Marc Jan} and Ren{\'e} Luijk and Zhernakova, {Daria V} and Matthijs Moed and Patrick Deelen and Martijn Vermaat and {van Iterson}, Maarten and {van Dijk}, Freerk and {van Galen}, Michiel and Jan Bot and Slieker, {Roderick C} and Jhamai, {P Mila} and Michael Verbiest and Suchiman, {H Eka D} and Marijn Verkerk and {van der Breggen}, Ruud and {van Rooij}, Jeroen and Nico Lakenberg and Wibowo Arindrarto and Kielbasa, {Szymon M} and Iris Jonkers and {van 't Hof}, Peter and Irene Nooren and Marian Beekman and Joris Deelen and {van Heemst}, Diana and Alexandra Zhernakova and Tigchelaar, {Ettje F} and Swertz, {Morris a.} and Albert Hofman and Uitterlinden, {Andr{\'e} G} and Ren{\'e} Pool and {van Dongen}, J. and Hottenga, {Jouke J} and Stehouwer, {Coen D A} and {van der Kallen}, {Carla J H} and Schalkwijk, {Casper G} and {van den Berg}, {Leonard H} and {van Zwet}, {Erik W} and Hailiang Mei and Yang Li and Mathieu Lemire and Hudson, {Thomas J} and Slagboom, {P. Eline} and Cisca Wijmenga and Veldink, {Jan H} and {Van Greevenbroek}, {Marleen J.} and {van Duijn}, {Cornelia M} and Boomsma, {Dorret I} and Aaron Isaacs and {BIOS Consortium}",

year = "2017",

month = jan,

doi = "10.1038/ng.3721",

language = "English",

volume = "49",

pages = "131--138",

journal = "Nature Genetics",

issn = "1061-4036",

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Bonder, MJ, Luijk, R, Zhernakova, DV, Moed, M, Deelen, P, Vermaat, M, van Iterson, M, van Dijk, F, van Galen, M, Bot, J, Slieker, RC, Jhamai, PM, Verbiest, M, Suchiman, HED, Verkerk, M, van der Breggen, R, van Rooij, J, Lakenberg, N, Arindrarto, W, Kielbasa, SM, Jonkers, I, van 't Hof, P, Nooren, I, Beekman, M, Deelen, J, van Heemst, D, Zhernakova, A, Tigchelaar, EF, Swertz, MA, Hofman, A, Uitterlinden, AG, Pool, R , van Dongen, J , Hottenga, JJ, Stehouwer, CDA, van der Kallen, CJH, Schalkwijk, CG, van den Berg, LH, van Zwet, EW, Mei, H, Li, Y, Lemire, M, Hudson, TJ, Slagboom, PE, Wijmenga, C, Veldink, JH, Van Greevenbroek, MJ, van Duijn, CM, Boomsma, DI, Isaacs, A & BIOS Consortium 2017, 'Disease variants alter transcription factor levels and methylation of their binding sites', Nature Genetics, vol. 49, no. 1, pp. 131-138. https://doi.org/10.1038/ng.3721

TY - JOUR

T1 - Disease variants alter transcription factor levels and methylation of their binding sites

AU - Bonder, Marc Jan

AU - Luijk, René

AU - Zhernakova, Daria V

AU - Moed, Matthijs

AU - Deelen, Patrick

AU - Vermaat, Martijn

AU - van Iterson, Maarten

AU - van Dijk, Freerk

AU - van Galen, Michiel

AU - Bot, Jan

AU - Slieker, Roderick C

AU - Jhamai, P Mila

AU - Verbiest, Michael

AU - Suchiman, H Eka D

AU - Verkerk, Marijn

AU - van der Breggen, Ruud

AU - van Rooij, Jeroen

AU - Lakenberg, Nico

AU - Arindrarto, Wibowo

AU - Kielbasa, Szymon M

AU - Jonkers, Iris

AU - van 't Hof, Peter

AU - Nooren, Irene

AU - Beekman, Marian

AU - Deelen, Joris

AU - van Heemst, Diana

AU - Zhernakova, Alexandra

AU - Tigchelaar, Ettje F

AU - Swertz, Morris a.

AU - Hofman, Albert

AU - Uitterlinden, André G

AU - Pool, René

AU - van Dongen, J.

AU - Hottenga, Jouke J

AU - Stehouwer, Coen D A

AU - van der Kallen, Carla J H

AU - Schalkwijk, Casper G

AU - van den Berg, Leonard H

AU - van Zwet, Erik W

AU - Mei, Hailiang

AU - Li, Yang

AU - Lemire, Mathieu

AU - Hudson, Thomas J

AU - Slagboom, P. Eline

AU - Wijmenga, Cisca

AU - Veldink, Jan H

AU - Van Greevenbroek, Marleen J.

AU - van Duijn, Cornelia M

AU - Boomsma, Dorret I

AU - Isaacs, Aaron

AU - BIOS Consortium

PY - 2017/1

Y1 - 2017/1

N2 - Most disease-associated genetic variants are noncoding, making it challenging to design experiments to understand their functional consequences. Identification of expression quantitative trait loci (eQTLs) has been a powerful approach to infer the downstream effects of disease-associated variants, but most of these variants remain unexplained. The analysis of DNA methylation, a key component of the epigenome, offers highly complementary data on the regulatory potential of genomic regions. Here we show that disease-associated variants have widespread effects on DNA methylation in trans that likely reflect differential occupancy of trans binding sites by cis-regulated transcription factors. Using multiple omics data sets from 3,841 Dutch individuals, we identified 1,907 established trait-associated SNPs that affect the methylation levels of 10,141 different CpG sites in trans (false discovery rate (FDR) < 0.05). These included SNPs that affect both the expression of a nearby transcription factor (such as NFKB1, CTCF and NKX2-3) and methylation of its respective binding site across the genome. Trans methylation QTLs effectively expose the downstream effects of disease-associated variants.

AB - Most disease-associated genetic variants are noncoding, making it challenging to design experiments to understand their functional consequences. Identification of expression quantitative trait loci (eQTLs) has been a powerful approach to infer the downstream effects of disease-associated variants, but most of these variants remain unexplained. The analysis of DNA methylation, a key component of the epigenome, offers highly complementary data on the regulatory potential of genomic regions. Here we show that disease-associated variants have widespread effects on DNA methylation in trans that likely reflect differential occupancy of trans binding sites by cis-regulated transcription factors. Using multiple omics data sets from 3,841 Dutch individuals, we identified 1,907 established trait-associated SNPs that affect the methylation levels of 10,141 different CpG sites in trans (false discovery rate (FDR) < 0.05). These included SNPs that affect both the expression of a nearby transcription factor (such as NFKB1, CTCF and NKX2-3) and methylation of its respective binding site across the genome. Trans methylation QTLs effectively expose the downstream effects of disease-associated variants.

KW - Journal Article

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UR - http://www.scopus.com/inward/citedby.url?scp=85002263457&partnerID=8YFLogxK

U2 - 10.1038/ng.3721

DO - 10.1038/ng.3721

M3 - Article

C2 - 27918535

SN - 1061-4036

VL - 49

SP - 131

EP - 138

JO - Nature Genetics

JF - Nature Genetics

IS - 1

ER -

Disease variants alter transcription factor levels and methylation of their binding sites

Abstract

Funding

Keywords

Cohort Studies

UN SDGs

Access to Document

Persistent URL (handle)

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