Evidence points to early life as a critical period of heightened susceptibility to factors that alter the risk of later-life non-communicable diseases. Two early life risk factors increasingly recognised as important for adult health are early puberty timing and childhood obesity. Both factors are influenced by the environment, as demonstrated by their rapid increase in prevalence over time, but their susceptibility is also largely genetically determined. This thesis aimed to investigate the genetic determinants of these early life factors to improve understanding of their underlying biology and links to later life health using a combination of analytical approaches.

First, this thesis identified six genes in which rare heterozygous loss-of-function variants impact puberty timing (KDM4C, MC3R, MKRN3, PDE10A, TACR3, ZNF483) by performing an exome-wide association study on recalled age at menarche (N~220,000) and age at voice breaking (N~180,000) in the UK Biobank. To better understand which biological factors influence puberty timing, I used a Mendelian randomisation approach to infer the causal effects of sex hormones and markers of glucose metabolism on puberty timing in girls and boys. Higher testosterone bioactivity, insulin-like growth factor 1 bioaction and insulin resistance appeared to promote earlier puberty timing in both sexes.

Next, the relationship between childhood adiposity and puberty timing was investigated. Using longitudinal childhood body weight data from the Norwegian Mother, Father and Child cohort study and a clustering approach, I found that 55% of the common genetic signals for age at menarche primarily affect puberty with no effect on early-life weight, whereas 45% are also related to changes in early-life weight before puberty onset. Both early weight-related and weight-unrelated mechanisms drive the link between early puberty timing and later-life outcomes.

Given the close relationship between childhood adiposity and female puberty timing, I applied a multi-variate modelling approach, Genomic Structural Equation Modelling, to various childhood adiposity-related phenotypes, including age at menarche, to boost power for the discovery of childhood adiposity loci. This approach identified 526 loci robustly associated with childhood adiposity, several displaying differing effects on adiposity across the life course. The implicated genes pointed to known biological pathways in the central nervous system but also to the pancreas and insulin signalling. Lastly, building on the observation of age-specific adiposity loci, I performed an exome-wide association study on both comparative body size age 10 (N~414,000) and adult body mass index (N~420,000) in the UK Biobank, identifying female-specific adult obesity genes (DIDO1, PTPRG, SLC12A5) as well as genes with childhood-specific effects (MADD, OBSCN). Several of these genes suggest roles of neuron death, apoptosis and deoxyribonucleic acid damage response mechanisms in obesity susceptibility across the life course.

In summary, this thesis provides novel insights into the genetic architecture of puberty timing and adiposity across the life course, highlighting biological mechanisms underlying these traits and the trajectories linking them to later life health. These findings provide directions for future research and inform putative interventions targeting early puberty timing and childhood obesity as part of a life course approach to preventing non-communicable diseases.