Extensive Variation and Low Heritability of DNA Methylation Identified in a Twin Study

Overview

Journal Genome Res

Specialty Genetics

Date 2011 Sep 28

PMID 21948560

Citations 30

Authors

Kristina Gervin

Martin Hammero

Hanne E Akselsen

Rune Moe

Heidi Nygard

Ingunn Brandt

Hakon K Gjessing

Jennifer R Harris

Dag E Undlien

Robert Lyle

Affiliations

Soon will be listed here.

Abstract

Disturbance of DNA methylation leading to aberrant gene expression has been implicated in the etiology of many diseases. Whereas variation at the genetic level has been studied extensively, less is known about the extent and function of epigenetic variation. To explore variation and heritability of DNA methylation, we performed bisulfite sequencing of 1760 CpG sites in 186 regions in the human major histocompatibility complex (MHC) in CD4+ lymphocytes from 49 monozygotic (MZ) and 40 dizygotic (DZ) twin pairs. Individuals show extensive variation in DNA methylation both between and within regions. In addition, many regions also have a complex pattern of variation. Globally, there appears to be a bimodal distribution of DNA methylation in the regions, but a significant fraction of the CpG sites are also heterogeneously methylated. Classification of regions into CpG islands (intragenic and intergenic), 5' end of genes not associated with a defined CpG island, conserved noncoding regions, and random CpG sites shows region-type differences in variation and heritability. Analyses revealed slightly lower intra-pair differences among MZ than among DZ pairs, suggesting some genetic influences on DNA methylation variation, with most of the variance attributed to nongenetic factors. Overall, heritability estimates of DNA methylation were low. Our heritability estimates are, however, somewhat deflated due to the presence of batch effects that artificially inflate the estimates of shared environment.

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References

Schneider E, Pliushch G, El Hajj N, Galetzka D, Puhl A, Schorsch M . Spatial, temporal and interindividual epigenetic variation of functionally important DNA methylation patterns. Nucleic Acids Res. 2010; 38(12):3880-90. PMC: 2896520. DOI: 10.1093/nar/gkq126. View

Hewagama A, Richardson B . The genetics and epigenetics of autoimmune diseases. J Autoimmun. 2009; 33(1):3-11. PMC: 2819418. DOI: 10.1016/j.jaut.2009.03.007. View

Cropley J, Suter C, Martin D . Methyl donors change the germline epigenetic state of the A(vy) allele. FASEB J. 2007; 21(12):3021. DOI: 10.1096/07-1002. View

Irizarry R, Ladd-Acosta C, Wen B, Wu Z, Montano C, Onyango P . The human colon cancer methylome shows similar hypo- and hypermethylation at conserved tissue-specific CpG island shores. Nat Genet. 2009; 41(2):178-186. PMC: 2729128. DOI: 10.1038/ng.298. View

Flanagan J, Popendikyte V, Pozdniakovaite N, Sobolev M, Assadzadeh A, Schumacher A . Intra- and interindividual epigenetic variation in human germ cells. Am J Hum Genet. 2006; 79(1):67-84. PMC: 1474120. DOI: 10.1086/504729. View

Boomsma D, Busjahn A, Peltonen L . Classical twin studies and beyond. Nat Rev Genet. 2002; 3(11):872-82. DOI: 10.1038/nrg932. View

Traherne J . Human MHC architecture and evolution: implications for disease association studies. Int J Immunogenet. 2008; 35(3):179-92. PMC: 2408657. DOI: 10.1111/j.1744-313X.2008.00765.x. View

Harris J, Tambs K, Magnus P . Sex-specific effects for body mass index in the new Norwegian twin panel. Genet Epidemiol. 1995; 12(3):251-65. DOI: 10.1002/gepi.1370120303. View

Fryer A, Emes R, Ismail K, Haworth K, Mein C, Carroll W . Quantitative, high-resolution epigenetic profiling of CpG loci identifies associations with cord blood plasma homocysteine and birth weight in humans. Epigenetics. 2010; 6(1):86-94. PMC: 3052917. DOI: 10.4161/epi.6.1.13392. View

10.

. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature. 2007; 447(7145):661-78. PMC: 2719288. DOI: 10.1038/nature05911. View

11.

Bernstein B, Meissner A, Lander E . The mammalian epigenome. Cell. 2007; 128(4):669-81. DOI: 10.1016/j.cell.2007.01.033. View

12.

Weber M, Hellmann I, Stadler M, Ramos L, Paabo S, Rebhan M . Distribution, silencing potential and evolutionary impact of promoter DNA methylation in the human genome. Nat Genet. 2007; 39(4):457-66. DOI: 10.1038/ng1990. View

13.

Rakyan V, Hildmann T, Novik K, Lewin J, Tost J, Cox A . DNA methylation profiling of the human major histocompatibility complex: a pilot study for the human epigenome project. PLoS Biol. 2004; 2(12):e405. PMC: 529316. DOI: 10.1371/journal.pbio.0020405. View

14.

Bock C, Walter J, Paulsen M, Lengauer T . Inter-individual variation of DNA methylation and its implications for large-scale epigenome mapping. Nucleic Acids Res. 2008; 36(10):e55. PMC: 2425484. DOI: 10.1093/nar/gkn122. View

15.

Craddock N, Hurles M, Cardin N, Pearson R, Plagnol V, Robson S . Genome-wide association study of CNVs in 16,000 cases of eight common diseases and 3,000 shared controls. Nature. 2010; 464(7289):713-20. PMC: 2892339. DOI: 10.1038/nature08979. View

16.

Harris J, Magnus P, Tambs K . The Norwegian Institute of Public Health Twin Panel: a description of the sample and program of research. Twin Res. 2003; 5(5):415-23. DOI: 10.1375/136905202320906192. View

17.

Heijmans B, Kremer D, Tobi E, Boomsma D, Slagboom P . Heritable rather than age-related environmental and stochastic factors dominate variation in DNA methylation of the human IGF2/H19 locus. Hum Mol Genet. 2007; 16(5):547-54. DOI: 10.1093/hmg/ddm010. View

18.

Boks M, Derks E, Weisenberger D, Strengman E, Janson E, Sommer I . The relationship of DNA methylation with age, gender and genotype in twins and healthy controls. PLoS One. 2009; 4(8):e6767. PMC: 2747671. DOI: 10.1371/journal.pone.0006767. View

19.

Lewin J, Schmitt A, Adorjan P, Hildmann T, Piepenbrock C . Quantitative DNA methylation analysis based on four-dye trace data from direct sequencing of PCR amplificates. Bioinformatics. 2004; 20(17):3005-12. DOI: 10.1093/bioinformatics/bth346. View

20.

Fraga M, Ballestar E, Paz M, Ropero S, Setien F, Ballestar M . Epigenetic differences arise during the lifetime of monozygotic twins. Proc Natl Acad Sci U S A. 2005; 102(30):10604-9. PMC: 1174919. DOI: 10.1073/pnas.0500398102. View