Examining Causal Determinants of Childhood Obesity and Pubertal Timing
Childhood obesity is a rapidly escalating public health crisis, with prevalence rates increasing from 4% in 1975 to 18% in 2016 among children aged 5-19 years worldwide. This rise in obesity may contribute to the secular trend towards earlier pubertal development on a global scale. Both childhood obesity and early pubertal timing are linked to increased risks of various physical and mental health complications. This thesis aims to explore the genetic and hormonal factors influencing childhood obesity and pubertal timing through various analytical approaches. I first explored the associations between eating behaviour and growth across infancy and childhood. Using the Children’s Eating Behaviour Questionnaire (CEBQ), I assessed eight appetitive traits—four food-approach and four food-avoidant traits—against growth velocities including weight, length/height, BMI, and body fat percentage. Notably, the significant appetitive traits with growth had stronger associations with body fat percentage compared to other growth measures, suggesting a specific link between these traits and adiposity rather than overall body size. Additionally, the findings showed broadly consistent associations between eating behaviour and the growth velocities across both infancy and childhood. I estimated the causal effects of various early life factors and growth metrics on pubertal timing in both girls and boys. Using Mendelian randomization (MR) techniques, I examined factors such as birthweight, height and adiposity at age 10, and sedentary behaviours. Higher birthweight conferred later pubertal timing in both sexes, while greater childhood height and adiposity conferred earlier pubertal timing. Interestingly, adiposity had a more pronounced effect in girls, whereas height had a stronger effect in boys. Additionally, sedentary behaviours were associated with earlier pubertal timing in both sexes. All of these associations appeared to be independent of adiposity. These findings suggest that early life factors, including potentially modifiable exposures, have likely causal effects on pubertal timing in both sexes. I further employed MR to investigate the effects of hormonal biomarkers on adiposity across different life stages. By introducing 'biological effect' filtering within MR, I explored whether genetic variants linked to higher biomarker concentrations indicate increased biomarker action or biomarker resistance and separated these variants. The analysis identified distinct effects of hormonal bioaction and resistance when applied to fasting insulin and IGF-1. For instance, insulin resistance was negatively associated with both childhood and adult adiposity, while IGF-1 resistance was negatively associated with childhood adiposity. These findings underscore the complex and varied roles of hormonal regulation in adiposity Finally, I examined the effect of recombinant human growth hormone (rhGH) therapy on pubertal timing by systematically reviewing and pooling data from 25 published studies using inverse-variance-weighted fixed and random effects models. The analysis revealed that rhGH promoted earlier pubertal timing, shorter pubertal duration, and reduced pubertal growth in children with idiopathic short stature (ISS), but not in children with other conditions such as chronic renal failure (CRF) or small for gestational age (SGA). This indicates that the effects of rhGH vary depending on the underlying medical condition. The earlier onset of puberty in children with ISS could potentially limit the effectiveness of rhGH in increasing adult height by shortening the growth period during childhood. In summary, this thesis utilizes diverse data types and analytical methods to enhance the understanding of childhood obesity and pubertal timing, integrating both genetic and hormonal data. Gaining insights into the factors influencing childhood obesity and pubertal timing will inform future strategies for prevention. Addressing these issues early can reduce the need for medical interventions, improve the quality of life for affected children, and mitigate long-term economic and societal consequences associated with obesity-related health challenges.
Childhood obesity, Pubertal timing, Biomarkers
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