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.
Highlights
We performed genome-wide association study meta-analysis to identify genetic determinants of skeletal age (SA) deviating in multiple growth disorders
The severity and clinical features of congenital adrenal hyperplasia (CAH) depend on the severity of the enzymatic defect, which can occur in any of the five steroidogenic enzymes: cytochrome P450 side-chain cleavage enzyme encoded by CYP11A1; 21-α-hydroxylase encoded by CYP21A2; 3β-hydroxysteroid dehydrogenase 2 encoded by HSD3B2; 17-hydroxylase/17, 20-lyase encoded by CYP17A1 and 11-β-hydroxylase encoded by the CYP11B15
A genome-wide association study (GWAS) meta-analysis including 9,806,907 singlenucleotide polymorphisms (SNPs) was performed in 4557 children of multiethnic background participating in the Generation R Study (N = 3510, 49% boys; mean age 9.8, SD = 0.33 years) and the Bone Mineral Density in Childhood Study (BMDCS) (N = 1047, 47% boys; mean age 10.9, SD = 1.39 years) to identify loci associated with SA
Summary
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). Division of Orthopedic Surgery, Children’s Hospital Los Angeles, Keck School of Medicine, University of Southern California, 1975 Zonal Ave, Los Angeles, CA 90033, USA. Different disorders resulting in impairments of skeletal maturation and often associated with short stature are caused by loss of function mutations in diverse genes. A GWAS of SA will provide further insight into the underlying biology of human skeletal maturation and associated disorders of short stature. We metaanalyzed our two unpublished GWAS of SA in children of school age
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