title: Association of season of birth with DNA methylation and allergic disease.
abstract: Season of birth influences allergy risk; however, the biological mechanisms underlying this observation are unclear. The environment affects DNA methylation, with potentially long-lasting effects on gene expression and disease. This study examined whether DNA methylation could underlie the association between season of birth and allergy.
  
  
  
  In a subset of 18-year-old participants from the Isle of Wight (IoW) birth cohort (n = 367), the risks of birth season on allergic outcomes were estimated. Whole blood epigenome-wide DNA methylation was measured, and season-associated CpGs detected using a training-and-testing-based technique. Validation method examined the 8-year-old Prevention and Incidence of Asthma and Mite Allergy (PIAMA) cohort. The relationships between DNA methylation, season of birth and allergy were examined. CpGs were analysed in IoW third-generation cohort newborns.
  
  
  
  Autumn birth increased risk of eczema, relative to spring birth. Methylation at 92 CpGs showed association with season of birth in the epigenome-wide association study. In validation, significantly more CpGs had the same directionality than expected by chance, and four were statistically significant. Season-associated methylation was enriched among networks relating to development, the cell cycle and apoptosis. Twenty CpGs were nominally associated with allergic outcomes. Two CpGs were marginally on the causal pathway to allergy. Season-associated methylation was largely absent in newborns, suggesting it arises post-natally.
  
  
  
  This study demonstrates that DNA methylation in adulthood is associated with season of birth, supporting the hypothesis that DNA methylation could mechanistically underlie the effect of season of birth on allergy, although other mechanisms are also likely to be involved.
authors.affiliation: Human Development and Health, Faculty of Medicine, University of Southampton, Southampton, UK.
authors.forename: G A
authors.initials: GA
authors.lastname: Lockett
authors.affiliation: Division of Epidemiology, Biostatistics and Environmental Health, School of Public Health, University of Memphis, Memphis, TN, USA.
authors.forename: N
authors.initials: N
authors.lastname: Soto-Ramírez
authors.affiliation: Division of Epidemiology, Biostatistics and Environmental Health, School of Public Health, University of Memphis, Memphis, TN, USA.
authors.forename: M A
authors.initials: MA
authors.lastname: Ray
authors.affiliation: Department of Epidemiology and Biostatistics, Arnold School of Public Health, University of South Carolina, Columbia, SC, USA.
authors.forename: T M
authors.initials: TM
authors.lastname: Everson
authors.affiliation: Department of Pulmonology, GRIAC Research Institute, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.|Department of Genetics, GRIAC Research Institute, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
authors.forename: C-J
authors.initials: CJ
authors.lastname: Xu
authors.affiliation: The David Hide Asthma and Allergy Research Centre, Isle of Wight, UK.|Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, UK.
authors.forename: V K
authors.initials: VK
authors.lastname: Patil
authors.affiliation: Division of Epidemiology, Biostatistics and Environmental Health, School of Public Health, University of Memphis, Memphis, TN, USA.
authors.forename: W
authors.initials: W
authors.lastname: Terry
authors.affiliation: Division of Epidemiology, Biostatistics and Environmental Health, School of Public Health, University of Memphis, Memphis, TN, USA.
authors.forename: A
authors.initials: A
authors.lastname: Kaushal
authors.affiliation: Human Development and Health, Faculty of Medicine, University of Southampton, Southampton, UK.
authors.forename: F I
authors.initials: FI
authors.lastname: Rezwan
authors.affiliation: Department of Large Animal Clinical Sciences, Michigan State University, East Lansing, MI, USA.
authors.forename: S L
authors.initials: SL
authors.lastname: Ewart
authors.affiliation: Institute for Risk Assessment Sciences, Division of Environmental Epidemiology, Utrecht University, Utrecht, the Netherlands.
authors.forename: U
authors.initials: U
authors.lastname: Gehring
authors.affiliation: Department of Pulmonary Medicine and Tuberculosis, GRIAC Research Institute, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
authors.forename: D S
authors.initials: DS
authors.lastname: Postma
authors.affiliation: Department of Pediatric Pulmonology and Pediatric Allergology, Beatrix Children's Hospital, GRIAC Research Institute, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
authors.forename: G H
authors.initials: GH
authors.lastname: Koppelman
authors.affiliation: The David Hide Asthma and Allergy Research Centre, Isle of Wight, UK.|Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, UK.
authors.forename: S H
authors.initials: SH
authors.lastname: Arshad
authors.affiliation: Division of Epidemiology, Biostatistics and Environmental Health, School of Public Health, University of Memphis, Memphis, TN, USA.
authors.forename: H
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Division of Epidemiology, Biostatistics and Environmental Health, School of Public Health, University of Memphis, Memphis, TN, USA.
authors.forename: W
authors.initials: W
authors.lastname: Karmaus
authors.affiliation: Human Development and Health, Faculty of Medicine, University of Southampton, Southampton, UK.|Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, UK.
authors.forename: J W
authors.initials: JW
authors.lastname: Holloway
mesh_terms: D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D018899:CpG Islands; D019175:DNA Methylation; D004198:Disease Susceptibility; D005260:Female; D006801:Humans; D006967:Hypersensitivity / Q000453:epidemiology* / Q000209:etiology*; D007073:Immunoglobulin E / Q000097:blood / Q000276:immunology; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D018811:Maternal Exposure; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D015203:Reproducibility of Results; D012621:Seasons
chemical_list: D007073:Immunoglobulin E
keywords: 450K array; DNA methylation; epigenetics; epigenome-wide association study; season of birth