CYP11B1 variants influence skeletal maturation via alternative splicing

Olja Grgic, Matthew R. Gazzara, Alessandra Chesi, Carolina Medina-Gomez, Diana L. Cousminer, Jonathan A. Mitchell, Vid Prijatelj, Jard de Vries, Enisa Shevroja, Shana E. McCormack, Heidi J. Kalkwarf, Joan M. Lappe, Vicente Gilsanz, Sharon E. Oberfield, John A. Shepherd, Andrea Kelly, Soroosh Mahboubi, Fabio R. Faucz, Richard A. Feelders, Frank H. de JongAndre G. Uitterlinden, Jenny A. Visser, Louis R. Ghanem, Eppo B. Wolvius, Leo J. Hofland, Constantine A. Stratakis, Babette S. Zemel, Yoseph Barash, Struan F.A. Grant, Fernando Rivadeneira*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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We performed genome-wide association study meta-analysis to identify genetic determinants of skeletal age (SA) deviating in multiple growth disorders. The joint meta-analysis (N = 4557) in two multiethnic cohorts of school-aged children identified one locus, CYP11B1 (expression confined to the adrenal gland), robustly associated with SA (rs6471570-A; β = 0.14; P = 6.2 × 10−12). rs6410 (a synonymous variant in the first exon of CYP11B1 in high LD with rs6471570), was prioritized for functional follow-up being second most significant and the one closest to the first intron-exon boundary. In 208 adrenal RNA-seq samples from GTEx, C-allele of rs6410 was associated with intron 3 retention (P = 8.11 × 10−40), exon 4 inclusion (P = 4.29 × 10−34), and decreased exon 3 and 5 splicing (P = 7.85 × 10−43), replicated using RT-PCR in 15 adrenal samples. As CYP11B1 encodes 11-β-hydroxylase, involved in adrenal glucocorticoid and mineralocorticoid biosynthesis, our findings highlight the role of adrenal steroidogenesis in SA in healthy children, suggesting alternative splicing as a likely underlying mechanism.

Original languageEnglish
Article number1274
JournalCommunications Biology
Issue number1
Publication statusPublished - 9 Nov 2021

Bibliographical note

Funding Information:
We gratefully acknowledge the contribution of children and parents, research employees, general practitioners, hospitals, midwives, and pharmacies in Rotterdam and Philadelphia, involved in the Generation R Study and the Bone Mineral Density in Childhood Study. We also thank Dr. Scott Norton for his insights. The general design of Generation R Study is made possible by financial support from the Erasmus Medical Centre, Rotterdam, the Erasmus University Rotterdam, The Netherlands Organization for Health Research and Development (ZonMw), The Netherlands Organisation for Scientific Research (NWO), the Ministry of Health, Welfare and Sport. Additional grants supported this study: The Netherlands Organization for Health (ZonMw 907.00303, ZonMw 916.10159, ZonMw VIDI 016.136.361 to V.W.V.J., and ZonMw VIDI 016.136.367 to F.R. and C.M-G.). The BMDCS was funded by R01 HD58886; the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) contracts (N01-HD-1-3228, -3329, -3330, -3331, -3332, -3333) and the CTSA program Grant 8 UL1 TR000077. J.A.M. was supported by K01 HL123612. Additional support: NIH (R01 GM128096 and R01 AG046544 to Y.B. and M.R.G. and 1K99HD099330-01 to D.L.C.). GTEx project was supported by the Common Fund of the Office of the Director of the National Institutes of Health, and by NCI, NHGRI, NHLBI, NIDA, NIMH, and NINDS.

Publisher Copyright:
© 2021, The Author(s).


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