SUN-054 Genetic Studies of Height-Associated Protein Expression Levels in Childhood

Background: Genome-wide association studies (GWAS) have identified thousands of common genetic variants associated with human height, implicating hundreds of genes and loci. However, the mechanisms by which many of these genetic variants contribute to human adult height are still unknown. Integrating knowledge of the interaction between genetic background and protein levels in childhood can provide insights into the biology of human growth. Objective: To investigate biological associations at height-associated loci in the GH-IGF signaling pathway. Methods: We used data from the Cincinnati Genomic Control Cohort, a community-based cohort comprised of 1,020 children. The study was approved by the institutional review board at Cincinnati Children’s Hospital Medical Center. Protein levels for free and total IGF-I, intact and total IGFBP-3, PAPP-A2, IGF-II, and IGFBP-5 were measured by ELISA in 839 children (ages 3-18 years) and corrected for age- and sex-effects. We associated protein-level phenotypes using plink qassoc and stratified by sex and population, in ~870 European- and African-descent individuals. Meta-analyses were performed using the METAL fixed-effects model. GWAS of anthropometric traits were performed in the UK Biobank of ~400,000 individuals using Bolt-LMM, or curated from publicly available summary statistics. Results: We identified 17 independent genome-wide significant protein-level-associated loci (p<5x10(-8)). The most robust associations were previously identified expression quantitative trait loci (eQTLs). The IGFBP3 locus was associated with serum total IGFBP3 and IGF-II levels. Despite falling within a height locus, conditional analyses showed that the effect on IGFBP-3 protein levels was independent of the height signal (p=2.8e-31, post conditioning). However, conditional analyses showed that the protein level signal colocalizes with a known GWAS signal for sitting height ratio (SHR). The IGFBP5 locus was associated with IGFBP-5 protein levels and was also independent of height signals identified in the region (p=3.3e-32, post conditioning). Conclusions: We have identified novel pQTLs for IGF2, IGFBP3, and IGFBP5 that act independently from genetic signals in the same regions associated with adult height but may interact with related anthropometric traits including SHR. Additionally, this suggests that SNPs affecting adult height in these loci do not work via increasing serum levels of these proteins but rather through a different and undetermined mechanism.