A Genome-Wide Pharmacogenetic Study of Growth Hormone Responsiveness.

The Journal of clinical endocrinology and metabolism 2020 Oct 01

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Individual patients vary in their response to growth hormone (GH). No large-scale genome-wide studies have looked for genetic predictors of GH responsiveness. To identify genetic variants associated with GH responsiveness. Genome-wide association study (GWAS). Cohorts from multiple academic centers and a clinical trial. A total of 614 individuals from 5 short stature cohorts receiving GH: 297 with idiopathic short stature, 276 with isolated GH deficiency, and 65 born small for gestational age. Association of more than 2 million variants was tested. Primary analysis: individual single nucleotide polymorphism (SNP) association with first-year change in height standard deviation scores. Secondary analyses: SNP associations in clinical subgroups adjusted for clinical variables; association of polygenic score calculated from 697 genome-wide significant height SNPs with GH responsiveness. No common variant associations reached genome-wide 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. We performed the largest GWAS of GH responsiveness to date. We identified 2 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 GH responsiveness, likely distinct from the genetic regulators of adult height. © Endocrine Society 2020.

Citation

Andrew Dauber, Yan Meng, Laura Audi, Sailaja Vedantam, Benjamin Weaver, Antonio Carrascosa, Kerstin Albertsson-Wikland, Michael B Ranke, Alexander A L Jorge, Jose Cara, Michael P Wajnrajch, Anders Lindberg, Cecilia Camacho-Hübner, Joel N Hirschhorn. A Genome-Wide Pharmacogenetic Study of Growth Hormone Responsiveness. The Journal of clinical endocrinology and metabolism. 2020 Oct 01;105(10)