title: Identification of type 1 diabetes-associated DNA methylation variable positions that precede disease diagnosis.
abstract: Monozygotic (MZ) twin pair discordance for childhood-onset Type 1 Diabetes (T1D) is ∼50%, implicating roles for genetic and non-genetic factors in the aetiology of this complex autoimmune disease. Although significant progress has been made in elucidating the genetics of T1D in recent years, the non-genetic component has remained poorly defined. We hypothesized that epigenetic variation could underlie some of the non-genetic component of T1D aetiology and, thus, performed an epigenome-wide association study (EWAS) for this disease. We generated genome-wide DNA methylation profiles of purified CD14+ monocytes (an immune effector cell type relevant to T1D pathogenesis) from 15 T1D-discordant MZ twin pairs. This identified 132 different CpG sites at which the direction of the intra-MZ pair DNA methylation difference significantly correlated with the diabetic state, i.e. T1D-associated methylation variable positions (T1D-MVPs). We confirmed these T1D-MVPs display statistically significant intra-MZ pair DNA methylation differences in the expected direction in an independent set of T1D-discordant MZ pairs (P = 0.035). Then, to establish the temporal origins of the T1D-MVPs, we generated two further genome-wide datasets and established that, when compared with controls, T1D-MVPs are enriched in singletons both before (P = 0.001) and at (P = 0.015) disease diagnosis, and also in singletons positive for diabetes-associated autoantibodies but disease-free even after 12 years follow-up (P = 0.0023). Combined, these results suggest that T1D-MVPs arise very early in the etiological process that leads to overt T1D. Our EWAS of T1D represents an important contribution toward understanding the etiological role of epigenetic variation in type 1 diabetes, and it is also the first systematic analysis of the temporal origins of disease-associated epigenetic variation for any human complex disease.
authors: Blizard Institute of Cell and Molecular Science, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom. v.rakyan@qmul.ac.uk
authors: Vardhman K
authors: VK
authors: Rakyan
authors: Huriya
authors: H
authors: Beyan
authors: Thomas A
authors: TA
authors: Down
authors: Mohammed I
authors: MI
authors: Hawa
authors: Siarhei
authors: S
authors: Maslau
authors: Deeqo
authors: D
authors: Aden
authors: Antoine
authors: A
authors: Daunay
authors: Florence
authors: F
authors: Busato
authors: Charles A
authors: CA
authors: Mein
authors: Burkhard
authors: B
authors: Manfras
authors: Kerith-Rae M
authors: KR
authors: Dias
authors: Christopher G
authors: CG
authors: Bell
authors: Jörg
authors: J
authors: Tost
authors: Bernhard O
authors: BO
authors: Boehm
authors: Stephan
authors: S
authors: Beck
authors: R David
authors: RD
authors: Leslie
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D018899:CpG Islands / Q000235:genetics*; D019175:DNA Methylation / Q000235:genetics*; D003922:Diabetes Mellitus, Type 1 / Q000175:diagnosis / Q000235:genetics*; D044127:Epigenesis, Genetic / Q000235:genetics*; D057890:Epigenomics; D005260:Female; D005500:Follow-Up Studies; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D006801:Humans; D018950:Lipopolysaccharide Receptors / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000166:cytology / Q000378:metabolism*; D014430:Twins, Monozygotic
chemical_list: D018950:Lipopolysaccharide Receptors