CYP11B1 variants influence skeletal maturation via alternative splicing.
CYP11B1 variants influence skeletal maturation via alternative splicing.
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DOI：
10.1038/s42003-021-02774-y
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发表时间：
2021-11-09
影响因子：
5.9
通讯作者：
Rivadeneira F
中科院分区：
文献类型：
--
作者：
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
我们进行了全基因组关联研究的荟萃分析，以确定在多种生长障碍中骨龄(SA)偏离的遗传决定因素。在两个多民族学龄儿童队列中的联合Meta分析(N = 4557)发现了一个与SA(rs6471570-A；β = 0.14；P = 6.2×10−12)密切相关的基因座，即细胞色素P11B1(仅在肾上腺表达)。Rs6410(位于高LD的CYP11B1第一外显子的同义变异，与rs6471570)被优先用于功能随访，这是第二重要的，也是最接近第一内含子-外显子边界的。在2 0 8份GTEx肾上腺RNAseq样本中，rs6 410的C等位基因与内含子3保留(P = 8.11×10−4 0)、外显子4包涵体(P = 4.2 9×10−34)、外显子3和5剪接减少(P = 7.85×10−43)相关，并在15例肾上腺标本中复制。由于细胞色素P11B1编码11-β-羟基酶，参与肾上腺糖皮质激素和盐皮质激素的生物合成，我们的发现强调了肾上腺类固醇激素生成在健康儿童SA中的作用，提示选择性剪接可能是一种潜在的机制。Olja Gric，Matthew Gazzara和Alessandra Chesi等人。对两个儿科队列中的骨龄进行全基因组关联研究荟萃分析。他们观察到，肾上腺基因CYP11B1的变异影响了它的选择性剪接，这表明肾上腺类固醇激素的生成可能导致了其他健康儿童的骨龄变化。
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. Olja Grgic, Matthew Gazzara, and Alessandra Chesi et al. perform a genome-wide association study meta-analysis for skeletal age in two pediatric cohorts. They observe that variation in the adrenal gene, CYP11B1, impacts its alternative splicing, suggesting that adrenal steroidogenesis may contribute toward variation in skeletal age in otherwise healthy children.
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剪接的组织特异性遗传控制：对复杂性状的研究的影响。
影响因子：
9.8
作者：
Heinzen EL;Ge D;Cronin KD;Maia JM;Shianna KV;Gabriel WN;Welsh-Bohmer KA;Hulette CM;Denny TN;Goldstein DB
通讯作者：
Goldstein DB
影响因子：
30.8
作者：
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通讯作者：
Fuchsberger, Christian
影响因子：
3.3
作者：
James, Rebecca E.;Lukanova, Annekatrin;Kaaks, Rudolf
通讯作者：
Kaaks, Rudolf
影响因子：
5.8
作者：
Courant, Frederique;Aksglaede, Lise;Le Bizec, Bruno
通讯作者：
Le Bizec, Bruno
影响因子：
14.9
作者：
Kumar, Manjeet;Gouw, Marc;Gibson, Toby J.
通讯作者：
Gibson, Toby J.