Genome-wide association study and polygenic risk scores of serum DHEAS levels in a Chilean children cohort
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CONTEXT: Adrenarche reflects the developmental growth of the adrenal zona reticularis, which produces increasing adrenal androgen secretion (eg, dehydroepiandrosterone [DHEA]/dehydroepiandrosterone sulfate [DHEAS]) from approximately age 5 to 15 years. OBJECTIVE: We hypothesized that the study of the genetic determinants associated with variations in serum DHEAS during adrenarche might detect genetic variants influencing the rate or timing of this process. METHODS: Genome-wide genotyping was performed in participants of the Chilean pediatric Growth and Obesity Chilean Cohort Study (GOCS) cohort (n = 788). We evaluated the genetic determinants of DHEAS levels at the genome-wide level and in targeted genes associated with steroidogenesis. To corroborate our findings, we evaluated a polygenic risk score (PRS) for age at pubarche, based on the discovered variants, in children from the same cohort. RESULTS: We identified one significant variant at the genome-wide level in the full cohort, close to the GALR1 gene (P = 3.81 × 10-8). In addition, variants suggestive of association (P < 1 × 10-5) were observed in PRLR, PITX1, PTPRD, NR1H4, and BCL11B. Stratifying by sex, we found variants suggestive of association in SERBP1 and CAMTA1/VAMP3 for boys and near ZNF98, TRPC6, and SULT2A1 for girls. We also found significant reductions in age at pubarche in those children with higher PRS for greater DHEAS based on these newly identified variants. CONCLUSION: Our results disclose one variant associated with DHEAS concentrations at the level of genome-wide association study significance, and several variants with a suggestive association that may be involved in the genetic regulation of adrenarche.
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CYP17A1 catalyses the final step in the biosynthesis of the adrenal androgens DHEAS and ∆4-androstenedione.
“Remarkably, the ACTH+PRL combined treatment selectively increased the expression of CYP17A1 , encoding the CYP17A1 enzyme which catalyses the final step in the biosynthesis of the adrenal androgens DHEAS and ∆ 4androstenedione (Fig. 2A, 3).”
From ACTH and prolactin synergistically and selectively regulate CYP17 expression and adrenal androgen production in human foetal adrenal organ cultures (2023) · cites this paper as [38]
The Association Analysis section lists CYP17A1 among genes involved in adrenal steroidogenesis, but does not assign it the final biosynthetic step. The Genome-wide Association Study of Log-Dehydroepiandrosterone Sulfate section instead says SULT2A1 mediates the conversion of DHEA to DHEAS; it does not establish the claimed role for CYP17A1 in producing ∆4-androstenedione. Page numbers are unavailable in our copy. (LLM, conf=0.82)
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References 75 · Cited by 10
Research works printed but not linked: 1
- Chen F, Knecht K, Leu C, et al. Partial agonist/antagonist prop- erties of androstenedione and 4-androsten-3beta,17beta-diol. J Steroid Biochem Mol Biol. 2004;91(4-5):247-257.
- Authors
- Miranda, J. P., Lardone, M. C., Rodríguez, F., Cutler, G. B., Santos, J. L., Corvalán, C., Pereira, A., & Mericq, V.
- Affiliations
- Pontificia Universidad Católica de Chile (CL)
- University of Chile (CL)
- Gordon Cutler Consultancy LLC, Deltaville, Virginia, USA
- Institute of Maternal and Child Research, School of Medicine, Universidad de Chile, Santiago, Chile
- ORCID
- Venue
- The Journal of Clinical Endocrinology & Metabolism
- Publisher
- The Endocrine Society
- Published
- 2021-11-08
- Volume
- 107
- Issue
- 4
- Pages
- e1727-e1738
- ISSN
- 0021-972X (ISSN-L)
- 1945-7197
- OpenAlex
- W3211748951
- Cited by
- 10
- References
- 75
- Citations by year
- 2025: 4 · 2024: 2 · 2023: 3 · 2022: 1
- FWCI
- 0.85
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model (vor)
- Locations
- The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Fondo Nacional de Desarrollo Científico y Tecnológico (1120326, 1190346, 1140447, 1150416)
- Spanish National Cancer Research Centre
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Health Sciences › Medicine › Reproductive Medicine › Hypothalamic control of reproductive hormones
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Sexual Differentiation and Disorders
- Keywords
- adrenarche, galanin receptor 1, steroidogenesis, polygenic risk score, genetic factors, children, adrenal androgens, puberty timing, Chilean children
- MeSH terms
- Adolescent, Child, Child, Preschool, Chile, Female, Humans, Male, Risk Factors, Sulfates, Cohort Studies, Dehydroepiandrosterone Sulfate, Genome-Wide Association Study
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