A Genome-Wide Pharmacogenetic Study of Growth Hormone Responsiveness

• Published in: The journal of clinical endocrinology and metabolism 2020-10, Vol.105 (10), p.3203-3214
• Main Authors: Dauber, Andrew, Meng, Yan, Audi, Laura, Vedantam, Sailaja, Weaver, Benjamin, Carrascosa, Antonio, Albertsson-Wikland, Kerstin, Ranke, Michael B, Jorge, Alexander A L, Cara, Jose, Wajnrajch, Michael P, Lindberg, Anders, Camacho-Hübner, Cecilia, Hirschhorn, Joel N
• Format: Article
• Language: English
• Subjects: Body height; Body Height - drug effects; Body Height - genetics; Child; Clinical s; Cohort Studies; Drug therapy; Dwarfism, Pituitary - drug therapy; Dwarfism, Pituitary - genetics; Endocrinology and Diabetes; Endokrinologi och diabetes; Female; Galactosyltransferases - genetics; Genetic aspects; Genetic diversity; Genetic Loci; genome-wide association; Genome-wide association studies; Genome-Wide Association Study; Genomes; Growth disorders; growth hormone; Growth hormones; Human Growth Hormone - therapeutic use; Humans; Infant, Small for Gestational Age; Male; Molecular Chaperones - genetics; Pediatric research; Pharmacogenetics; Pharmacogenomic Testing - statistics & numerical data; Polymorphism, Single Nucleotide; Replication; short stature; Sialyltransferases - genetics; Single-nucleotide polymorphism; Small for gestational age; Somatotropin; Treatment Outcome
• ISSN: 0021-972X; 1945-7197; 1945-7197
• DOI: 10.1210/clinem/dgaa443

Abstract Context Individual patients vary in their response to growth hormone (GH). No large-scale genome-wide studies have looked for genetic predictors of GH responsiveness. Objective To identify genetic variants associated with GH responsiveness. Design Genome-wide association study (GWAS). Setting Cohorts from multiple academic centers and a clinical trial. Patients 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. Intervention Association of more than 2 million variants was tested. Main Outcome Measures 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. Results 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. Conclusions 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.