Pleiotropic genetic influence on birth weight and childhood obesity

Abstract

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.

Figure 1

Enrichment of four functional annotations among loci jointly associated with birth weight and childhood obesity traits. (A) European birth weight and childhood body mass index (BW_EU-CBMI), (B) European birth weight and childhood obesity (BW_EU-COB), (C) Trans-ethnic birth weight and childhood body mass index (BW_TR-CBMI), (D) Trans-ethnic birth weight and childhood obesity (BW_TR-COB). The bars denote the enrichment fold for variants that are associated jointly with BW and childhood obesity traits (red), only with birth weight (green), and only with childhood obesity traits (blue), respectively.

Figure 2

Regional plots of novel pleiotropic loci associated with birthweight and childhood obesity traits. (A) rs6887211 (EBF1) locus association with both birth weight and childhood body mass index (B) rs7958572 (LMRB1L) locus associated with both birthweight and childhood obesity or childhood body mass index. The horizontal axes cover a region 500 kb upstream and downstream from the reference SNP. The vertical axes denote the joint association probabilities of the SNPs with both birthweight and childhood obesity traits. The purple triangles denote the index SNPs (rs6887211 in EBF1 and rs7958572 in LMRB1L). All other colored points denote the surrounding SNPs in that region, and they are colored based on their linkage disequilibrium (r²) with the reference SNP. The box at the bottom shows genes that fall in the region.