Early Life Determinants of Metabolic and Reproductive Health
Events in early life have consistently been associated with health outcomes in later life. The ‘developmental origins’ theory first hypothesised that adverse conditions in-utero can lead to physiological adaptations in the developing foetus which have long lasting influences on health. This concept has been extended to early childhood and adolescence, whereby exposures during critical periods of development can impact health throughout the life course of an individual. In particular, a secular trend for a decreasing age of puberty onset has been linked to the global increases in prevalence of cardio-metabolic diseases and cancer. It has been suggested that childhood obesity and lifetime sex hormone exposure may act as key mediating factors in this relationship. As the prevalence of obesity continues to rise globally and consequent comorbidities place an increasing burden on healthcare systems, understanding the mechanisms that link early life events to later life health have become of increasing importance. While environmental exposures are often cited as being highly influential on growth and development, the role of genetics has become gradually more apparent in recent years. This has been aided by the availability of increasingly large data resources. Genetic studies have shown that many developmental traits are highly heritable and share genetic determinants with metabolic and reproductive health outcomes. In this thesis I use data from large-scale, population-based resources to further elucidate the role of genetic and epigenetic factors in explaining observed associations between developmental traits and later life metabolic and reproductive health. I begin by examining the genetic aetiology of puberty timing in men, a key stage of sexual development which is understudied compared to women. I identify 29 novel genes involved in the control of puberty timing, implicating new biological pathways and demonstrate genetic correlations between earlier age of puberty and adverse health in adulthood. I then expand on the theme of genetic discovery by conducting genome-wide association studies (GWAS) for reproductive traits in the UK Biobank study. These outcomes have important societal and public health impacts but many have not previously been investigated from a genetic perspective. I identify over 800 variant-trait associations, highlighting genomic regions with highly pleiotropic influences on a diverse range of reproductive traits. This data is then leveraged to construct a framework for conducting phenome-wide association studies (PheWAS), which is used to explore the extent to which both BMI and sex hormone exposure act as mediating factors to explain the link between earlier puberty and heightened reproductive health risks. I go on to examine mechanisms linking early life markers of development to adult health. I investigate the association between weight at birth and body composition in adulthood, determining that foetal and maternal-specific genetic determinants of birth weight have differential influences on fat and lean mass distribution. Downstream analyses suggest that these operate through distinct biological pathways, adding to our understanding of the association between low birth weight and poor health. Finally, I conduct an epigenome-wide association study (EWAS) as a complementary approach to GWAS for both BMI and puberty timing to identify additional genomic loci associated with both traits. Using EWAS data I present evidence for a casual epigenetic effect on puberty timing, functioning through both BMI-mediated and independent pathways. The findings from this thesis contribute to the understanding of the genetic determinants of early life developmental processes and their relationship with later health, which have important implications for the improvement of individualised disease prevention and management.
Genetics, Epidemiology, Growth, Development, Puberty
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