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

Marc Jan Bonder; Rene Luijk; Dania 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; Andre G. Uitterlinden; Rene Pool; Jenny 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 M. J. van Greevenbroek; Cornelia M. van Duijn; Dorret I. Boomsma; Aaron Isaacs; BIOS Consortium; Bastiaan T. Heijmans; Lude Franke

doi:10.1038/ng.3721

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

Marc Jan Bonder, Rene Luijk, Dania 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, Andre G. Uitterlinden, Rene Pool, Jenny 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 M. J. van Greevenbroek, Cornelia M. van Duijn, Dorret I. Boomsma, Aaron Isaacs, BIOS Consortium, Bastiaan T. Heijmans^*, Lude Franke^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

202 Downloads (Pure)

Abstract

Most disease-associated genetic variants are noncoding, making it challenging to design experiments to understand their functional consequences(1,2). 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(3,4). The analysis of DNA methylation, a key component of the epigenome(5,6), offers highly complementary data on the regulatory potential of genomic regions(7,8). 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	8
Journal	Nature Genetics
Volume	49
Issue number	1
DOIs	https://doi.org/10.1038/ng.3721
Publication status	Published - Jan 2017

Keywords

GENOME-WIDE ASSOCIATION
GENE-EXPRESSION
SUSCEPTIBILITY LOCI
ARCHITECTURE
PROTEINS
DNA
FAMILY

Access to Document

10.1038/ng.3721

Full text Final published version, 1.77 MBLicence: Taverne

Cite this

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., ... Franke, L. (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

@article{2046a4f0be494002a8572b4c3dc7aeaa,

title = "Disease variants alter transcription factor levels and methylation of their binding sites",

abstract = "Most disease-associated genetic variants are noncoding, making it challenging to design experiments to understand their functional consequences(1,2). 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(3,4). The analysis of DNA methylation, a key component of the epigenome(5,6), offers highly complementary data on the regulatory potential of genomic regions(7,8). 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 = "GENOME-WIDE ASSOCIATION, GENE-EXPRESSION, SUSCEPTIBILITY LOCI, ARCHITECTURE, PROTEINS, DNA, FAMILY",

author = "Bonder, {Marc Jan} and Rene Luijk and Zhernakova, {Dania 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, {Andre G.} and Rene Pool and {van Dongen}, Jenny 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 M. J.} and {van Duijn}, {Cornelia M.} and Boomsma, {Dorret I.} and Aaron Isaacs and {BIOS Consortium} and Heijmans, {Bastiaan T.} and Lude Franke",

year = "2017",

month = jan,

doi = "10.1038/ng.3721",

language = "English",

volume = "49",

pages = "131--138",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Publishing Group",

number = "1",

}

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, MMJ, van Duijn, CM, Boomsma, DI, Isaacs, A, BIOS Consortium, Heijmans, BT & Franke, L 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, Rene

AU - Zhernakova, Dania 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, Andre G.

AU - Pool, Rene

AU - van Dongen, Jenny

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 M. J.

AU - van Duijn, Cornelia M.

AU - Boomsma, Dorret I.

AU - Isaacs, Aaron

AU - BIOS Consortium

AU - Heijmans, Bastiaan T.

AU - Franke, Lude

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(1,2). 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(3,4). The analysis of DNA methylation, a key component of the epigenome(5,6), offers highly complementary data on the regulatory potential of genomic regions(7,8). 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(1,2). 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(3,4). The analysis of DNA methylation, a key component of the epigenome(5,6), offers highly complementary data on the regulatory potential of genomic regions(7,8). 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 - GENOME-WIDE ASSOCIATION

KW - GENE-EXPRESSION

KW - SUSCEPTIBILITY LOCI

KW - ARCHITECTURE

KW - PROTEINS

KW - DNA

KW - FAMILY

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 -