A Genomewide Pharmacogenetic Study of Growth Hormone Responsiveness.

Context Individual patients vary in their response to growth hormone (GH). No large scale genomewide studies have looked for genetic predictors of GH responsiveness. Objective To identify genetic variants associated with GH responsiveness. Design Genomewide association study. Setting Cohorts from multiple academic centers and a clinical trial. Patients 614 individuals receiving GH from 5 short stature cohorts: 297 with idiopathic short stature, 276 with isolated GH deficiency, and 65 born small for gestational age. Intervention Association of >2 million variants was tested. Main outcome measures Primary analysis: individual SNP association with 1st year change in height SDS. Secondary analyses: SNP associations in clinical subgroups adjusted for clinical variables; association of polygenic score calculated from 697 genomewide significant height SNPs with GH responsiveness. Results No common variant associations reached genomewide significance in the primary analysis. The strongest suggestive signals were found near the B4GALT4 and TBCE genes. After meta-analysis including replication data, signals at several loci reached or retained genome-wide significance in secondary analyses, including variants near ST3GAL6. There was no significant association with variants previously reported to be associated with GH response nor with a polygenic predicted height score. Conclusions We performed the largest genomewide association study of GH responsiveness to date. We identified two loci with a suggestive effect on GH responsiveness in our primary analysis, and several genome-wide significant associations in secondary analyses that require further replication. Our results are consistent with a polygenic component to growth hormone responsiveness, likely distinct from the genetic regulators of adult height.