Genome-wide CRISPR screening of chondrocyte maturation newly implicates genes in skeletal growth and height-associated GWAS loci.
Genome-wide CRISPR screening of chondrocyte maturation newly implicates genes in skeletal growth and height-associated GWAS loci.
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DOI：
10.1016/j.xgen.2023.100299
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发表时间：
2023-05-10
期刊：
影响因子：
--
通讯作者：
Renthal NE
中科院分区：
文献类型：
--
作者：
Baronas JM;Bartell E;Eliasen A;Doench JG;Yengo L;Vedantam S;Marouli E;GIANT Consortium;Kronenberg HM;Hirschhorn JN;Renthal NE
软骨细胞生长和成熟的改变可能导致人类身高的变化，包括骨骼生长的单基因疾病。我们的目的是通过将人类身高全基因组关联研究 (GWAS) 与体外生长板软骨细胞增殖和成熟的全基因组敲除 (KO) 筛选相结合，来确定与人类生长相关的基因和途径。我们鉴定了 145 个在培养的早期和/或晚期时间点改变软骨细胞增殖和成熟的基因，其中 90% 的基因在二次筛选中得到验证。这些基因富含单基因生长障碍基因和对骨骼生长和软骨内骨化至关重要的 KEGG 通路。此外，这些基因附近的常见变异捕获了独立于 GWAS 计算优先顺序的基因的身高遗传力。我们的研究强调了生物学相关组织的功能研究作为正交数据集的价值，以从 GWAS 中提炼可能的因果基因，并暗示软骨细胞增殖和成熟的新遗传调节因子。全基因组 CRISPR KO 研究将生长板成熟与身高 GWAS 联系起来 确定了 145 个影响软骨细胞增殖和成熟的基因 筛选目标独立预测 GWAS 身高遗传力的富集 方法可用于改进现有的 GWAS 基因分配算法 Baronas 等人。将人类身高 GWAS 与生长板软骨细胞的功能性全基因组筛选配对。目标在身高遗传力和对软骨内骨化至关重要的基因方面得到丰富。这项研究强调，相关组织的功能测定可以从 GWAS 中提炼可能的因果基因，并暗示软骨细胞成熟的新调节因子。
Alterations in the growth and maturation of chondrocytes can lead to variation in human height, including monogenic disorders of skeletal growth. We aimed to identify genes and pathways relevant to human growth by pairing human height genome-wide association studies (GWASs) with genome-wide knockout (KO) screens of growth-plate chondrocyte proliferation and maturation in vitro. We identified 145 genes that alter chondrocyte proliferation and maturation at early and/or late time points in culture, with 90% of genes validating in secondary screening. These genes are enriched in monogenic growth disorder genes and in KEGG pathways critical for skeletal growth and endochondral ossification. Further, common variants near these genes capture height heritability independent of genes computationally prioritized from GWASs. Our study emphasizes the value of functional studies in biologically relevant tissues as orthogonal datasets to refine likely causal genes from GWASs and implicates new genetic regulators of chondrocyte proliferation and maturation. Genome-wide CRISPR KO study links growth-plate maturation to height GWASs Identified 145 genes affecting chondrocyte proliferation and maturation Screening targets independently predict enrichment of GWAS height heritability Method could be used to improve existing GWAS gene assignment algorithms Baronas et al. paired human height GWASs with functional genome-wide screening of growth-plate chondrocytes. Targets were enriched in height heritability and genes critical for endochondral ossification. This study emphasizes that functional assays in relevant tissues can refine likely causal genes from GWASs and implicates new regulators of chondrocyte maturation.
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影响因子：
4.5
作者：
Bowen ME;Ayturk UM;Kurek KC;Yang W;Warman ML
通讯作者：
Warman ML
影响因子：
9.8
作者：
Gusev, Alexander;Lee, S. Hong;Price, Alkes L.
通讯作者：
Price, Alkes L.
影响因子：
46.9
作者：
Doench JG;Fusi N;Sullender M;Hegde M;Vaimberg EW;Donovan KF;Smith I;Tothova Z;Wilen C;Orchard R;Virgin HW;Listgarten J;Root DE
通讯作者：
Root DE
影响因子：
64.5
作者：
Boyle EA;Li YI;Pritchard JK
通讯作者：
Pritchard JK
DOI：
10.1016/0922-3371(90)90079-c
发表时间：
1990-05-01
期刊：
CELL DIFFERENTIATION AND DEVELOPMENT
影响因子：
--
作者：
ATSUMI, T;MIWA, Y;IKAWA, Y
通讯作者：
IKAWA, Y