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Birth weight associations with psychiatric and physical health, cognitive function, and DNA methylation differences in an adult population

By Rebecca A. Madden, Daniel L. McCartney, Rosie M. Walker, Robert F. Hillary, Mairead L. Bermingham, Konrad Rawlik, Stewart W Morris, Archie Campbell, David J. Porteous, Ian J Deary, Kathryn L. Evans, Jonathan Hafferty, Andrew M. McIntosh, Riccardo E. Marioni

Posted 09 Jun 2019
bioRxiv DOI: 10.1101/664045

Background The Developmental Origins of Adult Disease (DOAD) 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. Methods The Generation Scotland study allows data linkage to historic Scottish birth cohorts, and birth records held through the NHS Information and Statistics Division. Data linkage with these sources yielded a sample of 4, 710 individuals. Health measures were related to birth weight in regression models. An epigenome-wide association study (EWAS) was performed in a subgroup (n=1, 395), relating adult DNAm from whole blood to birth weight, with replication in an independent sample (n=362). Associations between birth weight and epigenetic clocks were also assessed. Findings Higher birth weight was significantly associated with reduced incidence of depression and osteoarthritis, higher body mass index, and higher general intelligence (absolute standardised effect size range 0·04 to 0·30, p(FDR)<0·05). Meta-analysis of discovery and replication EWAS studies yielded one genome-wide significant CpG site (p=5·97×10−9), cg00966482. Significant associations between birth weight and Grim Age (p=0·0014) and DNAm-derived telomere length (p=3·3×10−4) are also described. Interpretation Our results demonstrate associations between birth weight and adult health outcomes, with particularly striking effects for depression risk. It also provides support for an association between birth weight and DNAm, describing the first significant EWAS site associated with birth weight in an adult sample. Funding Wellcome Trust Strategic Award 104036/Z/14/Z Evidence before this study The associations between birth weight and various adult health outcomes have been well established. DNA methylation is a plausible mechanism through which early life experiences may continue to affect health throughout the lifecourse; however, evidence for birth weight associations with DNA methylation in adulthood has not yet been robustly established. This is likely due to small sample sizes of previous samples, as well as the use of poor-quality birth weight data, such as binary ‘low/normal’ variables or retrospective self-report. Alternatively, work has attempted to describe the persistence into adulthood of DNA methylation at sites identified at birth. Added value of this study We investigated genome-wide differential DNA methylation patterns from whole blood using data linkage-derived, continuous birth weight data, in the largest reported adult sample (n=1, 395) with replication (n=362) and meta-analysis. Meta-analysis revealed one epigenome-wide significant CpG site, to our knowledge the first significant EWAS result reported for birth weight in a an adult sample. In addition, we found associations between birth weight and GrimAge and a DNA methylation-derived measure of telomere length, demonstrating accelerated biological ageing in lower birth weight individuals. Together, these results suggest differential methylation exists in adulthood related to birth weight, and this may be relevant to health and mortality. Implications of all the available evidence Although CpG sites differentially methylated with birth weight at parturition may not remain so throughout life, the adult epigenome may still provide information on the impact of birth weight on health outcomes. The adult epigenome, therefore, may represent a useful archive of the foetal experience which results in birth weight variability, and this information may provide clinically useful information in mid-life. * DOAD : Developmental Origins of Adult Disease DNAm : DNA methylation EWAS : epigenome-wide association study BMI : body mass index GS : Generation Scotland OR : Odds Ratio SD : Standard Deviation SE : Standard Error CI : confidence interval SCID : Structured Clinical Interview for DSM-IV ACONF : Aberdeen Children of the 1950s AMND : Aberdeen Maternity and Neonatal Databank SMR : Scottish Morbidity Records HDL : high-density lipoprotein

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