CYP11B1 variants influence skeletal maturation via alternative splicing

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

doi:10.1038/s42003-021-02774-y

CYP11B1 variants influence skeletal maturation via alternative splicing

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 JongAndre 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^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

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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.

Original language	English
Article number	1274
Journal	Communications Biology
Volume	4
Issue number	1
DOIs	https://doi.org/10.1038/s42003-021-02774-y
Publication status	Published - 9 Nov 2021

Bibliographical note

Funding Information:
We gratefully acknowledge the contribution of children and parents, research employees, general practitioners, hospitals, midwives, and pharmacies in Rotterdam and Philadelphia, involved in the Generation R Study and the Bone Mineral Density in Childhood Study. We also thank Dr. Scott Norton for his insights. The general design of Generation R Study is made possible by financial support from the Erasmus Medical Centre, Rotterdam, the Erasmus University Rotterdam, The Netherlands Organization for Health Research and Development (ZonMw), The Netherlands Organisation for Scientific Research (NWO), the Ministry of Health, Welfare and Sport. Additional grants supported this study: The Netherlands Organization for Health (ZonMw 907.00303, ZonMw 916.10159, ZonMw VIDI 016.136.361 to V.W.V.J., and ZonMw VIDI 016.136.367 to F.R. and C.M-G.). The BMDCS was funded by R01 HD58886; the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) contracts (N01-HD-1-3228, -3329, -3330, -3331, -3332, -3333) and the CTSA program Grant 8 UL1 TR000077. J.A.M. was supported by K01 HL123612. Additional support: NIH (R01 GM128096 and R01 AG046544 to Y.B. and M.R.G. and 1K99HD099330-01 to D.L.C.). GTEx project was supported by the Common Fund of the Office of the Director of the National Institutes of Health, and by NCI, NHGRI, NHLBI, NIDA, NIMH, and NINDS.

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© 2021, The Author(s).

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CYP11B1 variants influence skeletal maturation via alternative splicingFinal published version, 1.29 MBLicence: CC BY

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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., ... Rivadeneira, F. (2021). CYP11B1 variants influence skeletal maturation via alternative splicing. Communications Biology, 4(1), Article 1274. https://doi.org/10.1038/s42003-021-02774-y

@article{087a3c84a6904612ac66b3cd9ff70fb8,

title = "CYP11B1 variants influence skeletal maturation via alternative splicing",

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.",

author = "Olja Grgic and Gazzara, {Matthew R.} and Alessandra Chesi and Carolina Medina-Gomez and Cousminer, {Diana L.} and Mitchell, {Jonathan A.} and Vid Prijatelj and {de Vries}, Jard and Enisa Shevroja and McCormack, {Shana E.} and Kalkwarf, {Heidi J.} and Lappe, {Joan M.} and Vicente Gilsanz and Oberfield, {Sharon E.} and Shepherd, {John A.} and Andrea Kelly and Soroosh Mahboubi and Faucz, {Fabio R.} and Feelders, {Richard A.} and {de Jong}, {Frank H.} and Uitterlinden, {Andre G.} and Visser, {Jenny A.} and Ghanem, {Louis R.} and Wolvius, {Eppo B.} and Hofland, {Leo J.} and Stratakis, {Constantine A.} and Zemel, {Babette S.} and Yoseph Barash and Grant, {Struan F.A.} and Fernando Rivadeneira",

note = "Funding Information: We gratefully acknowledge the contribution of children and parents, research employees, general practitioners, hospitals, midwives, and pharmacies in Rotterdam and Philadelphia, involved in the Generation R Study and the Bone Mineral Density in Childhood Study. We also thank Dr. Scott Norton for his insights. The general design of Generation R Study is made possible by financial support from the Erasmus Medical Centre, Rotterdam, the Erasmus University Rotterdam, The Netherlands Organization for Health Research and Development (ZonMw), The Netherlands Organisation for Scientific Research (NWO), the Ministry of Health, Welfare and Sport. Additional grants supported this study: The Netherlands Organization for Health (ZonMw 907.00303, ZonMw 916.10159, ZonMw VIDI 016.136.361 to V.W.V.J., and ZonMw VIDI 016.136.367 to F.R. and C.M-G.). The BMDCS was funded by R01 HD58886; the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) contracts (N01-HD-1-3228, -3329, -3330, -3331, -3332, -3333) and the CTSA program Grant 8 UL1 TR000077. J.A.M. was supported by K01 HL123612. Additional support: NIH (R01 GM128096 and R01 AG046544 to Y.B. and M.R.G. and 1K99HD099330-01 to D.L.C.). GTEx project was supported by the Common Fund of the Office of the Director of the National Institutes of Health, and by NCI, NHGRI, NHLBI, NIDA, NIMH, and NINDS. Publisher Copyright: {\textcopyright} 2021, The Author(s).",

year = "2021",

month = nov,

day = "9",

doi = "10.1038/s42003-021-02774-y",

language = "English",

volume = "4",

journal = "Communications Biology",

issn = "2399-3642",

publisher = "Springer Nature",

number = "1",

}

Grgic, O, Gazzara, MR, Chesi, A, Medina-Gomez, C, Cousminer, DL, Mitchell, JA, Prijatelj, V , de Vries, J, Shevroja, E, McCormack, SE, Kalkwarf, HJ, Lappe, JM, Gilsanz, V, Oberfield, SE, Shepherd, JA, Kelly, A, Mahboubi, S, Faucz, FR, Feelders, RA, de Jong, FH, Uitterlinden, AG , Visser, JA, Ghanem, LR, Wolvius, EB , Hofland, LJ, Stratakis, CA, Zemel, BS, Barash, Y, Grant, SFA & Rivadeneira, F 2021, 'CYP11B1 variants influence skeletal maturation via alternative splicing', Communications Biology, vol. 4, no. 1, 1274. https://doi.org/10.1038/s42003-021-02774-y

TY - JOUR

T1 - CYP11B1 variants influence skeletal maturation via alternative splicing

AU - Grgic, Olja

AU - Gazzara, Matthew R.

AU - Chesi, Alessandra

AU - Medina-Gomez, Carolina

AU - Cousminer, Diana L.

AU - Mitchell, Jonathan A.

AU - Prijatelj, Vid

AU - de Vries, Jard

AU - Shevroja, Enisa

AU - McCormack, Shana E.

AU - Kalkwarf, Heidi J.

AU - Lappe, Joan M.

AU - Gilsanz, Vicente

AU - Oberfield, Sharon E.

AU - Shepherd, John A.

AU - Kelly, Andrea

AU - Mahboubi, Soroosh

AU - Faucz, Fabio R.

AU - Feelders, Richard A.

AU - de Jong, Frank H.

AU - Uitterlinden, Andre G.

AU - Visser, Jenny A.

AU - Ghanem, Louis R.

AU - Wolvius, Eppo B.

AU - Hofland, Leo J.

AU - Stratakis, Constantine A.

AU - Zemel, Babette S.

AU - Barash, Yoseph

AU - Grant, Struan F.A.

AU - Rivadeneira, Fernando

N1 - Funding Information: We gratefully acknowledge the contribution of children and parents, research employees, general practitioners, hospitals, midwives, and pharmacies in Rotterdam and Philadelphia, involved in the Generation R Study and the Bone Mineral Density in Childhood Study. We also thank Dr. Scott Norton for his insights. The general design of Generation R Study is made possible by financial support from the Erasmus Medical Centre, Rotterdam, the Erasmus University Rotterdam, The Netherlands Organization for Health Research and Development (ZonMw), The Netherlands Organisation for Scientific Research (NWO), the Ministry of Health, Welfare and Sport. Additional grants supported this study: The Netherlands Organization for Health (ZonMw 907.00303, ZonMw 916.10159, ZonMw VIDI 016.136.361 to V.W.V.J., and ZonMw VIDI 016.136.367 to F.R. and C.M-G.). The BMDCS was funded by R01 HD58886; the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) contracts (N01-HD-1-3228, -3329, -3330, -3331, -3332, -3333) and the CTSA program Grant 8 UL1 TR000077. J.A.M. was supported by K01 HL123612. Additional support: NIH (R01 GM128096 and R01 AG046544 to Y.B. and M.R.G. and 1K99HD099330-01 to D.L.C.). GTEx project was supported by the Common Fund of the Office of the Director of the National Institutes of Health, and by NCI, NHGRI, NHLBI, NIDA, NIMH, and NINDS. Publisher Copyright: © 2021, The Author(s).

PY - 2021/11/9

Y1 - 2021/11/9

N2 - 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.

AB - 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.

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U2 - 10.1038/s42003-021-02774-y

DO - 10.1038/s42003-021-02774-y

M3 - Article

AN - SCOPUS:85118643896

SN - 2399-3642

VL - 4

JO - Communications Biology

JF - Communications Biology

IS - 1

M1 - 1274

ER -

CYP11B1 variants influence skeletal maturation via alternative splicing

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