title: A study of the influence of sex on genome wide methylation.
abstract: Sex differences in methylation status have been observed in specific gene-disease studies and healthy methylation variation studies, but little work has been done to study the impact of sex on methylation at the genome wide locus-to-locus level or to determine methods for accounting for sex in genomic association studies. In this study we investigate the genomic sex effect on saliva DNA methylation of 197 subjects (54 females) using 20,493 CpG sites. Three methods, two-sample T-test, principle component analysis and independent component analysis, all successfully identify sex influences. The results show that sex not only influences the methylation of genes in the X chromosome but also in autosomes. 580 autosomal sites show strong differences between males and females. They are found to be highly involved in eight functional groups, including DNA transcription, RNA splicing, membrane, etc. Equally important is that we identify some methylation sites associated with not only sex, but also other phenotypes (age, smoking and drinking level, and cancer). Verification was done through an independent blood cell DNA methylation data (1298 CpG sites from a cancer panel array). The same genomic site-specific influence pattern and potential confounding effects with cancer were observed. The overlapping rate of identified sex affected genes between saliva and blood cell is 81% for X chromosome, and 8% for autosomes. Therefore, correction for sex is necessary. We propose a simple correction method based on independent component analysis, which is a data driven method and accommodates sample differences. Comparison before and after the correction suggests that the method is able to effectively remove the potentially confounding effects of sex, and leave other phenotypes untouched. As such, our method is able to disentangle the sex influence on a genome wide level, and paves the way to achieve more accurate association analyses in genome wide methylation studies.
authors.affiliation: The Mind Research Network, Albuquerque, New Mexico, United States of America. jliu@mrn.org
authors.forename: Jingyu
authors.initials: J
authors.lastname: Liu
authors.forename: Marilee
authors.initials: M
authors.lastname: Morgan
authors.forename: Kent
authors.initials: K
authors.lastname: Hutchison
authors.forename: Vince D
authors.initials: VD
authors.lastname: Calhoun
mesh_terms: D002875:Chromosomes; D041321:Chromosomes, Human, X; D019175:DNA Methylation; D005260:Female; D015894:Genome, Human; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D008722:Methods; D025341:Principal Component Analysis; D012737:Sex Factors
references.citation: Nat Neurosci. 2009 Mar;12(3):342-8
references.pmid: 19234457
references.citation: J Abnorm Psychol. 1982 Jun;91(3):199-209
references.pmid: 7096790
references.citation: Neural Comput. 1995 Nov;7(6):1129-59
references.pmid: 7584893
references.citation: Cell Biol Toxicol. 2008 Jun;24(3):265-72
references.pmid: 17929180
references.citation: Genome Biol. 2003;4(5):P3
references.pmid: 12734009
references.citation: Br J Haematol. 2005 Dec;131(5):632-5
references.pmid: 16351640
references.citation: Am J Med Genet B Neuropsychiatr Genet. 2008 Jul 5;147B(5):565-70
references.pmid: 18454435
references.citation: Mol Oncol. 2009 Dec;3(5-6):425-38
references.pmid: 19497796
references.citation: Genome Res. 2006 Mar;16(3):383-93
references.pmid: 16449502
references.citation: PLoS Biol. 2004 Dec;2(12):e405
references.pmid: 15550986
references.citation: Leukemia. 2006 Jan;20(1):149-51
references.pmid: 16307009
references.citation: Leukemia. 2007 Sep;21(9):1937-44
references.pmid: 17611569
references.citation: Methods Mol Biol. 2009;507:3-20
references.pmid: 18987802
references.citation: Nat Protoc. 2009;4(1):44-57
references.pmid: 19131956
references.citation: Mol Cancer. 2006 Jul 18;5:28
references.pmid: 16848908
references.citation: Ann Surg Oncol. 2008 Nov;15(11):3272-7
references.pmid: 18712569
references.citation: Cancer Res. 2003 Jun 15;63(12):3043-8
references.pmid: 12810624
references.citation: Ann Med. 2006;38(8):530-44
references.pmid: 17438668
references.citation: Hum Genet. 2005 Aug;117(4):402-3
references.pmid: 15928902
references.citation: Hum Mol Genet. 2006 Nov 1;15(21):3132-45
references.pmid: 16984965
references.citation: Epigenetics. 2006 Oct-Dec;1(4):e1-11
references.pmid: 17486179
references.citation: Cancer Epidemiol Biomarkers Prev. 1999 Jun;8(6):501-6
references.pmid: 10385139
references.citation: Am J Surg Pathol. 2007 Feb;31(2):240-6
references.pmid: 17255769
references.citation: Hum Brain Mapp. 2009 Jan;30(1):241-55
references.pmid: 18072279
references.citation: Ann Hum Genet. 2004 May;68(Pt 3):196-204
references.pmid: 15180700
references.citation: Nat Genet. 2006 Dec;38(12):1378-85
references.pmid: 17072317
references.citation: Cancer Res. 2008 Jun 1;68(11):4116-22
references.pmid: 18519670
references.citation: Mod Pathol. 2009 Jul;22(7):872-8
references.pmid: 19363472
references.citation: Hum Genet. 2007 Dec;122(5):505-14
references.pmid: 17851693