A Genome-Wide Pharmacogenetic Study of Growth Hormone Responsiveness
Dauber, Andrew (Division of Endocrinology, Children's National Hospital)
Meng, Yan (Broad Institute of MIT and Harvard)
Audí, Laura (Hospital Universitari Vall d'Hebron)
Vedantam, Sailaja (Broad Institute of MIT and Harvard)
Weaver, Benjamin (Broad Institute of MIT and Harvard)
Carrascosa Lezcano, Antonio 1949- (Hospital Universitari Vall d'Hebron)
Albertsson-Wikland, Kerstin (Department of Physiology/Endocrinology, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg)
Ranke, Michael B. (University Children's Hospital, Paediatric Endocrinology)
Jorge, Alexander A. L. (Unidade de Endocrinologia do Desenvolvimento (LIM42), Hospital das Clinicas da Faculdade de Medicina da Universidade de Sao Paulo)
Cara, Jose (Pfizer Inc, Rare Disease)
Wajnrajch, Michael P. (Pfizer Inc, Rare Disease)
Lindberg, Anders (Pfizer Inc, Data Management)
Camacho-Hübner, Cecilia (Pfizer Inc, Rare Disease)
Hirschhorn, Joel N. (Broad Institute of MIT and Harvard)
Universitat Autònoma de Barcelona

Date:	2020
Abstract:	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.
Rights:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Language:	Anglès
Document:	Article ; recerca ; Versió publicada
Subject:	Growth hormone ; Pharmacogenetics ; Short stature ; Genome-wide association
Published in:	The journal of clinical endocrinology & metabolism, Vol. 105 (july 2020) , p. 3203-3214, ISSN 1945-7197

DOI: 10.1210/clinem/dgaa443
PMID: 32652002

12 p, 3.3 MB

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