Year: 2021
Type: article
Study design: Observational Study
Abstract: 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.
Source: Communications Biology
Authors: 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 Jong, Andre 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
Institutions: Erasmus MC, University of Pennsylvania, Children's Hospital of Philadelphia, Centre Hospitalier Universitaire Vaudois, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Creighton University, University of Southern California, Children's Hospital of Los Angeles, Morgan Stanley Children's Hospital, Columbia University Irving Medical Center, University of Hawaii Cancer Center, National Institutes of Health, Eunice Kennedy Shriver National Institute of Child Health and Human Development
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $3,290
Funders: ZonMw, Erasmus Universiteit Rotterdam, Nederlandse Organisatie voor Wetenschappelijk Onderzoek, National Institute on Aging, National Heart, Lung, and Blood Institute, National Institute of General Medical Sciences, National Institute of Child Health and Human Development, National Center for Advancing Translational Sciences, Eunice Kennedy Shriver National Institute of Child Health and Human Development
Awards: G1260873166, G127234364, G1324243109, G1516964218, G1537059618, G2169357564, G3120757552, G3666122139, G3805357244, Genome Wide Association Study of Bone Mineral Accretion During Childhood, G4104009944, G5224277619, G6002092336, G6383967859, G6520203987, G6884148207, G7594226962, Sleep, Energetic Behaviors, and Adolescent Obesity during the Transition from Middle to High School, G80777371, G8258022698, G8771147827, G999904650
OpenAlex ID: W3212914766