Pleiotropic genetic influence on birth weight and childhood obesity.

Childhood obesity is a global public health problem. Understanding the molecular mechanisms that underlie early origins of childhood obesity can facilitate interventions. Consistent phenotypic and genetic correlations have been found between childhood obesity traits and birth weight (a proxy for in-utero growth), suggesting shared genetic influences (pleiotropy). We aimed to (1) investigate whether there is significant shared genetic influence between birth weight and childhood obesity traits, and (2) to identify genetic loci with shared effects. Using a statistical approach that integrates summary statistics and functional annotations for paired traits, we found strong evidence of pleiotropy (P < 3.53 × 10-127) and enrichment of functional annotations (P < 1.62 × 10-39) between birth weight and childhood body mass index (BMI)/obesity. The pleiotropic loci were enriched for regulatory features in skeletal muscle, adipose and brain tissues and in cell lines derived from blood lymphocytes. At 5% false discovery rate, 6 loci were associated with birth weight and childhood BMI and 13 loci were associated with birth weight and childhood obesity. Out of these 19 loci, one locus (EBF1) was novel to childhood obesity and one locus (LMBR1L) was novel to both birth weight and childhood BMI/obesity. These findings give evidence of substantial shared genetic effects in the regulation of both fetal growth and childhood obesity.