title: Genome-wide site-specific differential methylation in the blood of individuals with Klinefelter syndrome.
abstract: Klinefelter syndrome (KS) (47 XXY) is a common sex-chromosome aneuploidy with an estimated prevalence of one in every 660 male births. Investigations into the associations between DNA methylation and the highly variable clinical manifestations of KS have largely focused on the supernumerary X chromosome; systematic investigations of the epigenome have been limited. We obtained genome-wide DNA methylation data from peripheral blood using the Illumina HumanMethylation450K platform in 5 KS (47 XXY) versus 102 male (46 XY) and 113 female (46 XX) control subjects participating in the COPDGene Study. Empirical Bayes-mediated models were used to test for differential methylation by KS status. CpG sites with a false-discovery rate < 0.05 in the discovery cohort which were available on the first-generation HumanMethylation 27 K platform were further examined in an independent replication cohort of 2 KS subjects, 590 male, and 495 female controls drawn from the International COPD Genetics Network (ICGN). Differential methylation at sites throughout the genome were identified, including 86 CpG sites that were differentially methylated in KS subjects relative to both male and female controls. CpG sites annotated to the HEN1 methyltransferase homolog 1 (HENMT1), calcyclin-binding protein (CACYBP), and GTPase-activating protein (SH3 domain)-binding protein 1 (G3BP1) genes were among the "KS-specific" loci that were replicated in ICGN. We conclude that site-specific differential methylation exists throughout the genome in KS. The functional impact and clinical relevance of these differentially methylated loci should be explored in future studies.
authors.affiliation: Channing Division of Network Medicine, Brigham & Women's Hospital, Boston, Massachusetts.|Division of Pulmonary and Critical Care, Brigham & Women's Hospital, Boston, Massachusetts.
authors.forename: Emily S
authors.initials: ES
authors.lastname: Wan
authors.affiliation: Channing Division of Network Medicine, Brigham & Women's Hospital, Boston, Massachusetts.
authors.forename: Weiliang
authors.initials: W
authors.lastname: Qiu
authors.affiliation: Channing Division of Network Medicine, Brigham & Women's Hospital, Boston, Massachusetts.
authors.forename: Jarrett
authors.initials: J
authors.lastname: Morrow
authors.affiliation: Department of Biostatistics and Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland.
authors.forename: Terri H
authors.initials: TH
authors.lastname: Beaty
authors.affiliation: Department of Biostatistics and Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Hetmanski
authors.affiliation: Division of Pulmonary, Critical Care and Sleep Medicine, National Jewish Health, Denver, Colorado.
authors.forename: Barry J
authors.initials: BJ
authors.lastname: Make
authors.affiliation: Wolfson Institute for Biomedical Research, University College London, London, United Kingdom.
authors.forename: David A
authors.initials: DA
authors.lastname: Lomas
authors.affiliation: Channing Division of Network Medicine, Brigham & Women's Hospital, Boston, Massachusetts.|Division of Pulmonary and Critical Care, Brigham & Women's Hospital, Boston, Massachusetts.
authors.forename: Edwin K
authors.initials: EK
authors.lastname: Silverman
authors.affiliation: Channing Division of Network Medicine, Brigham & Women's Hospital, Boston, Massachusetts.|Division of Pulmonary and Critical Care, Brigham & Women's Hospital, Boston, Massachusetts.
authors.forename: Dawn L
authors.initials: DL
authors.lastname: DeMeo
mesh_terms: D000368:Aged; D001773:Blood Cells / Q000378:metabolism*; D016022:Case-Control Studies; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005260:Female; D015894:Genome, Human; D006801:Humans; D007713:Klinefelter Syndrome / Q000097:blood* / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D012737:Sex Factors