| Source: |
Grgic, O, Gazzara, M R, Chesi, A, Medina-Gomez, C, Cousminer, D L, Mitchell, J A, Prijatelj, V, de Vries, J, Shevroja, E, McCormack, S E, Kalkwarf, H J, Lappe, J M, Gilsanz, V, Oberfield, S E, Shepherd, J A, Kelly, A, Mahboubi, S, Faucz, F R, Feelders, R A, de Jong, F H, Uitterlinden, A G, Visser, J A, Ghanem, L R, Wolvius, E B, Hofland, L J, Stratakis, C A, Zemel, B S, Barash, Y, Grant, S F A & Rivadeneira, F 2021, 'CYP11B1 variants influence skeletal maturation via alternative splicing', Communications Biology, vol. 4, no. 1, 1274. .... |
| Description: |
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. |