title: Epigenome-wide DNA methylation in hearing ability: new mechanisms for an old problem.
abstract: Epigenetic regulation of gene expression has been shown to change over time and may be associated with environmental exposures in common complex traits. Age-related hearing impairment is a complex disorder, known to be heritable, with heritability estimates of 57-70%. Epigenetic regulation might explain the observed difference in age of onset and magnitude of hearing impairment with age. Epigenetic epidemiology studies using unrelated samples can be limited in their ability to detect small effects, and recent epigenetic findings in twins underscore the power of this well matched study design. We investigated the association between venous blood DNA methylation epigenome-wide and hearing ability. Pure-tone audiometry (PTA) and Illumina HumanMethylation array data were obtained from female twin volunteers enrolled in the TwinsUK register. Two study groups were explored: first, an epigenome-wide association scan (EWAS) was performed in a discovery sample (n=115 subjects, age range: 47-83 years, Illumina 27 k array), then replication of the top ten associated probes from the discovery EWAS was attempted in a second unrelated sample (n=203, age range: 41-86 years, Illumina 450 k array). Finally, a set of monozygotic (MZ) twin pairs (n = 21 pairs) within the discovery sample (Illumina 27 k array) was investigated in more detail in an MZ discordance analysis. Hearing ability was strongly associated with DNA methylation levels in the promoter regions of several genes, including TCF25 (cg01161216, p = 6.6 × 10(-6)), FGFR1 (cg15791248, p = 5.7 × 10(-5) and POLE (cg18877514, p= 6.3 × 10(-5)). Replication of these results in a second sample confirmed the presence of differential methylation at TCF25 (p(replication)=6 × 10(-5)) and POLE (p(replication) =0.016). In the MZ discordance analysis, twins' intrapair difference in hearing ability correlated with DNA methylation differences at ACP6 (cg01377755, r= -0.75, p=1.2 × 10(-4)) and MEF2D (cg08156349, r= -0.75, p=1.4 × 10(-4)). Examination of gene expression in skin, suggests an influence of differential methylation on expression, which may account for the variation in hearing ability with age.
authors.affiliation: Department of Twin Research and Genetic Epidemiology, King's College London, London, United Kingdom.
authors.forename: Lisa E
authors.initials: LE
authors.lastname: Wolber
authors.affiliation: Department of Twin Research and Genetic Epidemiology, King's College London, London, United Kingdom.
authors.forename: Claire J
authors.initials: CJ
authors.lastname: Steves
authors.affiliation: Department of Twin Research and Genetic Epidemiology, King's College London, London, United Kingdom.
authors.forename: Pei-Chien
authors.initials: PC
authors.lastname: Tsai
authors.affiliation: William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom; King Abdulaziz University, Jeddah, Saudi Arabia; Wellcome Trust Sanger Institute, Hinxton, Cambridge, United Kingdom.
authors.forename: Panos
authors.initials: P
authors.lastname: Deloukas
authors.affiliation: Department of Twin Research and Genetic Epidemiology, King's College London, London, United Kingdom.
authors.forename: Tim D
authors.initials: TD
authors.lastname: Spector
authors.affiliation: Department of Twin Research and Genetic Epidemiology, King's College London, London, United Kingdom.
authors.forename: Jordana T
authors.initials: JT
authors.lastname: Bell
authors.affiliation: Department of Twin Research and Genetic Epidemiology, King's College London, London, United Kingdom.
authors.forename: Frances M K
authors.initials: FM
authors.lastname: Williams
mesh_terms: D000135:Acid Phosphatase / Q000097:blood / Q000235:genetics; D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000097:blood* / Q000235:genetics / Q000473:pathology; D001301:Audiometry, Pure-Tone; D051792:Basic Helix-Loop-Helix Proteins / Q000097:blood / Q000235:genetics*; D019175:DNA Methylation; D004257:DNA Polymerase II / Q000097:blood / Q000235:genetics*; D044127:Epigenesis, Genetic; D005260:Female; D015894:Genome, Human; D006315:Hearing Loss, Functional / Q000097:blood* / Q000235:genetics / Q000503:physiopathology; D006801:Humans; D064326:MEF2 Transcription Factors / Q000097:blood / Q000235:genetics; D008875:Middle Aged; D000075223:Poly-ADP-Ribose Binding Proteins; D011401:Promoter Regions, Genetic; D019655:Quantitative Trait, Heritable; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000097:blood / Q000235:genetics*; D012097:Repressor Proteins / Q000097:blood / Q000235:genetics*; D014430:Twins, Monozygotic / Q000235:genetics
chemical_list: D000135:Acid Phosphatase; D051792:Basic Helix-Loop-Helix Proteins; D004257:DNA Polymerase II; D064326:MEF2 Transcription Factors; D000075223:Poly-ADP-Ribose Binding Proteins; D051496:Receptor, Fibroblast Growth Factor, Type 1; D012097:Repressor Proteins; C578043:MEF2D protein, human; C510400:TCF25 protein, human; C496348:FGFR1 protein, human; C119525:POLE protein, human; C459340:ACP6 protein, human