Communications biology · 2021
CYP11B1 variants influence skeletal maturation via alternative splicing.
СтатьяНазвание и аннотация: Перевод пока не подготовлен
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Grgic Olja, Gazzara Matthew R, Chesi Alessandra, Medina-Gomez Carolina, Cousminer Diana L, Mitchell Jonathan A, Prijatelj Vid, de Vries Jard, Shevroja Enisa, McCormack Shana E, Kalkwarf Heidi J, Lappe Joan M, Gilsanz Vicente, Oberfield Sharon E, Shepherd John A, Kelly Andrea, Mahboubi Soroosh, Faucz Fabio R, Feelders Richard A, de Jong Frank H, Uitterlinden Andre G, Visser Jenny A, Ghanem Louis R, Wolvius Eppo B, Hofland Leo J, Stratakis Constantine A, Zemel Babette S, Barash Yoseph, Grant Struan F A, Rivadeneira Fernando
Аннотация
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.