DNA methylation patterns associate with genetic and gene expression variation in HapMap cell lines.
BACKGROUND
DNA methylation is an essential epigenetic mechanism involved in gene regulation and disease, but little is known about the mechanisms underlying inter-individual variation in methylation profiles. Here we measured methylation levels at 22,290 CpG dinucleotides in lymphoblastoid cell lines from 77 HapMap Yoruba individuals, for which genome-wide gene expression and genotype data were also available.


RESULTS
Association analyses of methylation levels with more than three million common single nucleotide polymorphisms (SNPs) identified 180 CpG-sites in 173 genes that were associated with nearby SNPs (putatively in cis, usually within 5 kb) at a false discovery rate of 10%. The most intriguing trans signal was obtained for SNP rs10876043 in the disco-interacting protein 2 homolog B gene (DIP2B, previously postulated to play a role in DNA methylation), that had a genome-wide significant association with the first principal component of patterns of methylation; however, we found only modest signal of trans-acting associations overall. As expected, we found significant negative correlations between promoter methylation and gene expression levels measured by RNA-sequencing across genes. Finally, there was a significant overlap of SNPs that were associated with both methylation and gene expression levels.


CONCLUSIONS
Our results demonstrate a strong genetic component to inter-individual variation in DNA methylation profiles. Furthermore, there was an enrichment of SNPs that affect both methylation and gene expression, providing evidence for shared mechanisms in a fraction of genes.
Department of Human Genetics, The University of Chicago, Chicago, IL 60637, USA. jordana@well.ox.ac.uk
Jordana T
JT
Bell
Athma A
AA
Pai
Joseph K
JK
Pickrell
Daniel J
DJ
Gaffney
Roger
R
Pique-Regi
Jacob F
JF
Degner
Yoav
Y
Gilad
Jonathan K
JK
Pritchard
D002460:Cell Line; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005786:Gene Expression Regulation; D015894:Genome, Human; D055106:Genome-Wide Association Study; D005838:Genotype; D060148:HapMap Project; D006657:Histones / Q000378:metabolism; D006801:Humans; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D040641:Quantitative Trait Loci; D014158:Transcription, Genetic
D006657:Histones
Nature. 2007 Jun 14;447(7146):799-816
17571346
PLoS Genet. 2008 Oct;4(10):e1000214
18846210
Nucleic Acids Res. 2001 Jan 1;29(1):275-6
11125110
Nat Genet. 2009 Feb;41(2):178-186
19151715
Nature. 2010 Apr 1;464(7289):773-7
20220756
J Reprod Dev. 2009 Dec;55(6):607-14
19700929
J Biol Chem. 2007 Dec 21;282(51):37082-90
17971455
Genomics. 2010 Feb;95(2):73-83
20005943
Proc Natl Acad Sci U S A. 2003 Apr 15;100(8):4622-7
12671064
Nature. 2010 Apr 22;464(7292):1187-91
20237471
Curr Biol. 2004 Feb 17;14(4):R148-9
15027464
Am J Hum Genet. 2010 Mar 12;86(3):411-9
20215007
Science. 2010 Apr 9;328(5975):235-9
20299549
Nature. 2010 Apr 1;464(7289):768-72
20220758
Genome Res. 2010 Apr;20(4):440-6
20219944
Nature. 2010 Apr 15;464(7291):1082-6
20393567
Nat Rev Genet. 2009 May;10(5):295-304
19308066
J Nutr. 2009 Dec;139(12):2389-92
19812216
Am J Hum Genet. 2010 Feb 12;86(2):196-212
20159110
PLoS Genet. 2007 Jul;3(7):e114
17676998
PLoS Genet. 2007 May 18;3(5):e81
17511522
Nature. 2010 Apr 1;464(7289):704-12
19812545
Cancer Cell. 2004 Oct;6(4):361-71
15488759
Hum Mol Genet. 2004 Jan 15;13(2):247-55
14645199
Am J Hum Genet. 2007 Feb;80(2):221-31
17236128
Hum Mol Genet. 2007 Mar 1;16(5):547-54
17339271
Cancer Res. 2008 Apr 15;68(8):2726-35
18413740
Nat Genet. 2008 Jul;40(7):904-8
18568024
Nat Rev Genet. 2008 Dec;9(12):911-22
19002143
PLoS One. 2009 Aug 26;4(8):e6767
19774229
Nature. 2009 Dec 17;462(7275):868-74
20016592
Cell. 2004 Jun 11;117(6):721-33
15186774
Hum Genet. 2010 Jun;127(6):651-8
20238126
PLoS Genet. 2010 May 13;6(5):e1000952
20485568
J Mol Biol. 2005 May 20;348(5):1103-12
15854647
RNA. 2008 Jun;14(6):1005-11
18441047
Genome Res. 2010 Apr;20(4):434-9
20219945
PLoS Genet. 2008 Dec;4(12):e1000279
19057666
Nature. 2009 Nov 19;462(7271):315-22
19829295
Nat Genet. 2009 Feb;41(2):240-5
19151718
Nat Genet. 2007 Oct;39(10):1217-24
17873874
Nature. 2009 May 7;459(7243):108-12
19295514
Cancer Epidemiol Biomarkers Prev. 2005 Apr;14(4):938-43
15824167
Genome Res. 2011 Mar;21(3):447-55
21106904
Genome Res. 2008 Nov;18(11):1851-8
18714091
Genome Res. 2002 Apr;12(4):656-64
11932250
Nature. 2007 Oct 18;449(7164):851-61
17943122
JAMA. 2008 Jun 25;299(24):2877-83
18577732
PLoS Genet. 2006 Mar;2(3):e26
16520826
Genetics. 2008 Dec;180(4):1909-25
18791227
J Mol Biol. 1987 Jul 20;196(2):261-82
3656447
Nat Genet. 2007 Apr;39(4):457-66
17334365
Science. 2010 Apr 9;328(5975):232-5
20299548
FEBS Lett. 2005 Aug 15;579(20):4302-8
16051225
PLoS Genet. 2007 Sep;3(9):1724-35
17907809
PLoS Genet. 2008 Nov;4(11):e1000287
19043577
Genes Dev. 2008 Oct 1;22(19):2621-6
18805990
Hum Mol Genet. 2009 May 15;18(10):1755-68
19246518
Bioinformatics. 2003 Jan 22;19(2):185-93
12538238
Science. 2009 Sep 4;325(5945):1246-50
19644074
Nat Genet. 2006 Dec;38(12):1378-85
17072317
Nat Biotechnol. 2009 Apr;27(4):361-8
19329998