Autosomal genetic variation is associated with DNA methylation in regions variably escaping X-chromosome inactivation

Rene Luijk; Haoyu Wu; Cavin K. Ward-Caviness; Eilis Hannon; Elena Carnero-Montoro; Josine L. Min; Pooja Mandaviya; Martina Muller-Nurasyid; Hailiang Mei; Silvere M. van der Maarel; Caroline Relton; Jonathan Mill; Melanie Waldenberger; Jordana T. Bell; Rick Jansen; Alexandra Zhernakova; Lude Franke; Peter A. C. 't Hoen; Dorret I. Boomsma; Cornelia M. van Duijn; Marleen M. J. van Greevenbroek; Jan H. Veldink; Cisca Wijmenga; Joyce van Meurs; Lucia Daxinger; P. Eline Slagboom; Erik W. van Zwet; Bastiaan T. Heijmans; BIOS Consortium

doi:10.1038/s41467-018-05714-3

Autosomal genetic variation is associated with DNA methylation in regions variably escaping X-chromosome inactivation

Rene Luijk, Haoyu Wu, Cavin K. Ward-Caviness, Eilis Hannon, Elena Carnero-Montoro, Josine L. Min, Pooja Mandaviya, Martina Muller-Nurasyid, Hailiang Mei, Silvere M. van der Maarel, Caroline Relton, Jonathan Mill, Melanie Waldenberger, Jordana T. Bell, Rick Jansen, Alexandra Zhernakova, Lude Franke, Peter A. C. 't Hoen, Dorret I. Boomsma, Cornelia M. van DuijnMarleen M. J. van Greevenbroek, Jan H. Veldink, Cisca Wijmenga, Joyce van Meurs, Lucia Daxinger, P. Eline Slagboom, Erik W. van Zwet, Bastiaan T. Heijmans^*, BIOS Consortium

^*Corresponding author for this work

Interne Geneeskunde

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

Abstract

X-chromosome inactivation (XCI), i.e., the inactivation of one of the female X chromosomes, restores equal expression of X-chromosomal genes between females and males. However, similar to 10% of genes show variable degrees of escape from XCI between females, although little is known about the causes of variable XCI. Using a discovery data-set of 1867 females and 1398 males and a replication sample of 3351 females, we show that genetic variation at three autosomal loci is associated with female-specific changes in X-chromosome methylation. Through cis-eQTL expression analysis, we map these loci to the genes SMCHD1/METTL4, TRIM6/HBG2, and ZSCAN9. Low-expression alleles of the loci are predominantly associated with mild hypomethylation of CpG islands near genes known to variably escape XCI, implicating the autosomal genes in variable XCI. Together, these results suggest a genetic basis for variable escape from XCI and highlight the potential of a population genomics approach to identify genes involved in XCI.

Original language	English
Article number	3738
Number of pages	9
Journal	Nature Communications
Volume	9
DOIs	https://doi.org/10.1038/s41467-018-05714-3
Publication status	Published - 14 Sept 2018

Keywords

HUMAN GENOME
LINKED GENE
HISTONE H3
EXPRESSION
SMCHD1
VARIABILITY
OBJECTIVES
EPIGENOMES
ROTTERDAM
CLUSTERS
Humans
DNA Methylation/genetics
Male
Chromosomal Proteins, Non-Histone/genetics
Gene Expression Profiling
Genetic Variation
Female
Methyltransferases/genetics
Tripartite Motif Proteins/genetics
Gene Expression
gamma-Globins/genetics
DNA-Binding Proteins/genetics
CpG Islands
Ubiquitin-Protein Ligases/genetics
X Chromosome Inactivation/genetics

Access to Document

10.1038/s41467-018-05714-3Licence: CC BY

Cite this

Luijk, R., Wu, H., Ward-Caviness, C. K., Hannon, E., Carnero-Montoro, E., Min, J. L., Mandaviya, P., Muller-Nurasyid, M., Mei, H., van der Maarel, S. M., Relton, C., Mill, J., Waldenberger, M., Bell, J. T., Jansen, R., Zhernakova, A., Franke, L., 't Hoen, P. A. C., Boomsma, D. I., ... BIOS Consortium (2018). Autosomal genetic variation is associated with DNA methylation in regions variably escaping X-chromosome inactivation. Nature Communications, 9, Article 3738. https://doi.org/10.1038/s41467-018-05714-3

@article{4abdbe4b7ab44d84b320b38243d0cc76,

title = "Autosomal genetic variation is associated with DNA methylation in regions variably escaping X-chromosome inactivation",

abstract = "X-chromosome inactivation (XCI), i.e., the inactivation of one of the female X chromosomes, restores equal expression of X-chromosomal genes between females and males. However, similar to 10% of genes show variable degrees of escape from XCI between females, although little is known about the causes of variable XCI. Using a discovery data-set of 1867 females and 1398 males and a replication sample of 3351 females, we show that genetic variation at three autosomal loci is associated with female-specific changes in X-chromosome methylation. Through cis-eQTL expression analysis, we map these loci to the genes SMCHD1/METTL4, TRIM6/HBG2, and ZSCAN9. Low-expression alleles of the loci are predominantly associated with mild hypomethylation of CpG islands near genes known to variably escape XCI, implicating the autosomal genes in variable XCI. Together, these results suggest a genetic basis for variable escape from XCI and highlight the potential of a population genomics approach to identify genes involved in XCI.",

keywords = "HUMAN GENOME, LINKED GENE, HISTONE H3, EXPRESSION, SMCHD1, VARIABILITY, OBJECTIVES, EPIGENOMES, ROTTERDAM, CLUSTERS, Humans, DNA Methylation/genetics, Male, Chromosomal Proteins, Non-Histone/genetics, Gene Expression Profiling, Genetic Variation, Female, Methyltransferases/genetics, Tripartite Motif Proteins/genetics, Gene Expression, gamma-Globins/genetics, DNA-Binding Proteins/genetics, CpG Islands, Ubiquitin-Protein Ligases/genetics, X Chromosome Inactivation/genetics",

author = "Rene Luijk and Haoyu Wu and Ward-Caviness, {Cavin K.} and Eilis Hannon and Elena Carnero-Montoro and Min, {Josine L.} and Pooja Mandaviya and Martina Muller-Nurasyid and Hailiang Mei and {van der Maarel}, {Silvere M.} and Caroline Relton and Jonathan Mill and Melanie Waldenberger and Bell, {Jordana T.} and Rick Jansen and Alexandra Zhernakova and Lude Franke and {'t Hoen}, {Peter A. C.} and Boomsma, {Dorret I.} and {van Duijn}, {Cornelia M.} and {van Greevenbroek}, {Marleen M. J.} and Veldink, {Jan H.} and Cisca Wijmenga and {van Meurs}, Joyce and Lucia Daxinger and Slagboom, {P. Eline} and {van Zwet}, {Erik W.} and Heijmans, {Bastiaan T.} and {BIOS Consortium}",

year = "2018",

month = sep,

day = "14",

doi = "10.1038/s41467-018-05714-3",

language = "English",

volume = "9",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

}

Luijk, R, Wu, H, Ward-Caviness, CK, Hannon, E, Carnero-Montoro, E, Min, JL, Mandaviya, P, Muller-Nurasyid, M, Mei, H, van der Maarel, SM, Relton, C, Mill, J, Waldenberger, M, Bell, JT, Jansen, R, Zhernakova, A, Franke, L, 't Hoen, PAC, Boomsma, DI, van Duijn, CM, van Greevenbroek, MMJ, Veldink, JH, Wijmenga, C, van Meurs, J, Daxinger, L, Slagboom, PE, van Zwet, EW, Heijmans, BT & BIOS Consortium 2018, 'Autosomal genetic variation is associated with DNA methylation in regions variably escaping X-chromosome inactivation', Nature Communications, vol. 9, 3738. https://doi.org/10.1038/s41467-018-05714-3

TY - JOUR

T1 - Autosomal genetic variation is associated with DNA methylation in regions variably escaping X-chromosome inactivation

AU - Luijk, Rene

AU - Wu, Haoyu

AU - Ward-Caviness, Cavin K.

AU - Hannon, Eilis

AU - Carnero-Montoro, Elena

AU - Min, Josine L.

AU - Mandaviya, Pooja

AU - Muller-Nurasyid, Martina

AU - Mei, Hailiang

AU - van der Maarel, Silvere M.

AU - Relton, Caroline

AU - Mill, Jonathan

AU - Waldenberger, Melanie

AU - Bell, Jordana T.

AU - Jansen, Rick

AU - Zhernakova, Alexandra

AU - Franke, Lude

AU - 't Hoen, Peter A. C.

AU - Boomsma, Dorret I.

AU - van Duijn, Cornelia M.

AU - van Greevenbroek, Marleen M. J.

AU - Veldink, Jan H.

AU - Wijmenga, Cisca

AU - van Meurs, Joyce

AU - Daxinger, Lucia

AU - Slagboom, P. Eline

AU - van Zwet, Erik W.

AU - Heijmans, Bastiaan T.

AU - BIOS Consortium

PY - 2018/9/14

Y1 - 2018/9/14

N2 - X-chromosome inactivation (XCI), i.e., the inactivation of one of the female X chromosomes, restores equal expression of X-chromosomal genes between females and males. However, similar to 10% of genes show variable degrees of escape from XCI between females, although little is known about the causes of variable XCI. Using a discovery data-set of 1867 females and 1398 males and a replication sample of 3351 females, we show that genetic variation at three autosomal loci is associated with female-specific changes in X-chromosome methylation. Through cis-eQTL expression analysis, we map these loci to the genes SMCHD1/METTL4, TRIM6/HBG2, and ZSCAN9. Low-expression alleles of the loci are predominantly associated with mild hypomethylation of CpG islands near genes known to variably escape XCI, implicating the autosomal genes in variable XCI. Together, these results suggest a genetic basis for variable escape from XCI and highlight the potential of a population genomics approach to identify genes involved in XCI.

AB - X-chromosome inactivation (XCI), i.e., the inactivation of one of the female X chromosomes, restores equal expression of X-chromosomal genes between females and males. However, similar to 10% of genes show variable degrees of escape from XCI between females, although little is known about the causes of variable XCI. Using a discovery data-set of 1867 females and 1398 males and a replication sample of 3351 females, we show that genetic variation at three autosomal loci is associated with female-specific changes in X-chromosome methylation. Through cis-eQTL expression analysis, we map these loci to the genes SMCHD1/METTL4, TRIM6/HBG2, and ZSCAN9. Low-expression alleles of the loci are predominantly associated with mild hypomethylation of CpG islands near genes known to variably escape XCI, implicating the autosomal genes in variable XCI. Together, these results suggest a genetic basis for variable escape from XCI and highlight the potential of a population genomics approach to identify genes involved in XCI.

KW - HUMAN GENOME

KW - LINKED GENE

KW - HISTONE H3

KW - EXPRESSION

KW - SMCHD1

KW - VARIABILITY

KW - OBJECTIVES

KW - EPIGENOMES

KW - ROTTERDAM

KW - CLUSTERS

KW - Humans

KW - DNA Methylation/genetics

KW - Male

KW - Chromosomal Proteins, Non-Histone/genetics

KW - Gene Expression Profiling

KW - Genetic Variation

KW - Female

KW - Methyltransferases/genetics

KW - Tripartite Motif Proteins/genetics

KW - Gene Expression

KW - gamma-Globins/genetics

KW - DNA-Binding Proteins/genetics

KW - CpG Islands

KW - Ubiquitin-Protein Ligases/genetics

KW - X Chromosome Inactivation/genetics

U2 - 10.1038/s41467-018-05714-3

DO - 10.1038/s41467-018-05714-3

M3 - Article

C2 - 30218040

SN - 2041-1723

VL - 9

JO - Nature Communications

JF - Nature Communications

M1 - 3738

ER -