Birth weight associations with DNA methylation differences in an adult population

ABSTRACT

The Developmental Origins of Health and Disease (DOHaD) theory predicts that prenatal and early life events shape adult health outcomes. Birth weight is a useful indicator of the foetal experience and has been associated with multiple adult health outcomes. DNA methylation (DNAm) is one plausible mechanism behind the relationship of birth weight to adult health. Through data linkage between Generation Scotland and historic Scottish birth cohorts, and birth records held through the NHS Information and Statistics Division, a sample of 1,757 individuals with available birth weight and DNAm data was derived. Epigenome-wide association studies (EWAS) were performed in two independently generated DNAm subgroups (n_Set1 = 1,395, n_Set2 = 362), relating adult DNAm from whole blood to birth weight. Meta-analysis yielded one genome-wide significant CpG site (p = 5.97x10⁻⁹), cg00966482. There was minimal evidence for attenuation of the effect sizes for the lead loci upon adjustment for numerous potential confounder variables (body mass index, educational attainment, and socioeconomic status). Associations between birth weight and epigenetic measures of biological age were also assessed. Associations between lower birth weight and higher Grim Age acceleration (p_(FDR) = 3.6x10⁻³) and shorter DNAm-derived telomere length (p_(FDR) = 1.7x10⁻³) are described, although results for three other epigenetic clocks were null. Our results provide support for an association between birth weight and DNAm both locally at one CpG site, and globally via biological ageing estimates.

KEYWORDS:

• DNA methylation
• Generation Scotland
• birth weight
• depression
• EWAS

Acknowledgments

The authors thank all individuals and project team members who have contributed to both GS and to the ‘STRADL: Stratifying Resilience and Depression Longitudinally’ follow-up study.

Author contributions

Conception and design: RAM, JH, AMM, and REM. Data analysis: RAM and DLM. Interpretation: RAM, DLM, JH, AMM, REM. Drafting the article: RAM. Revision of the article: all authors.

Availability of data and materials

According to the terms of consent for Generation Scotland participants, access to data must be reviewed by the Generation Scotland Access Committee. Applications should be made to [email protected]. Summary statistics for the EWAS models will be made available on the University of Edinburgh DataShare facility upon acceptance https://doi.org/10.7488/ds/2876.

Disclosure statement

AMM has received research support from Eli Lilly, Janssen and the Sackler Trust. AMM has also received speaker fees from Janssen and Illumina. The other authors declare that they have no competing interests.

Supplementary material

Supplemental data for this article can be accessed here.

Additional information

Funding

GS received core support from the Chief Scientist Office of the Scottish Government Health Directorates (CZD/16/6) and the Scottish Funding Council (HR03006). Genotyping and DNA methylation profiling of the GS samples was carried out by the Genetics Core Laboratory at the Wellcome Trust Clinical Research Facility, Edinburgh, Scotland and was funded by the Medical Research Council UK and the Wellcome Trust (Wellcome Trust Strategic Award “STratifying Resilience And Depression Longitudinally” ((STRADL) Reference 104036/Z/14/Z). Data linkage was supported by MRC Mental Health Pathfinder Award (Reference MC_PC_17209). This work was conducted in the Centre for Cognitive Ageing and Cognitive Epidemiology, which is supported by the Medical Research Council and Biotechnology and Biological Sciences Research Council (MR/K026992/1). RAM and RFH are supported by funding from the Wellcome Trust 4-year PhD in Translational Neuroscience – training the next generation of basic neuroscientists to embrace clinical research [108890/Z/15/Z].