<p>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<sup>−12</sup>). 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<sup>−40</sup>), exon 4 inclusion (P = 4.29 × 10<sup>−34</sup>), and decreased exon 3 and 5 splicing (P = 7.85 × 10<sup>−43</sup>), 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.</p>

doi.org/10.1038/s42003-021-02774-y, hdl.handle.net/1765/137178
Communications Biology
Erasmus MC: University Medical Center Rotterdam

O. (Olja) Grgic, Matthew R. Gazzara, Alessandra Chesi, M.C. (Maria) Medina Gomez, Diana L. Cousminer, Jonathan A. Mitchell, … F. (Fernando) Rivadeneira. (2021). CYP11B1 variants influence skeletal maturation via alternative splicing. Communications Biology, 4(1). doi:10.1038/s42003-021-02774-y