Joint disease-specificity at the regulatory base-pair level.
Joint disease-specificity at the regulatory base-pair level.
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DOI：
10.1038/s41467-021-24345-9
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发表时间：
2021-07-06
影响因子：
16.6
通讯作者：
Capellini TD
中科院分区：
文献类型：
--
作者：
Muthuirulan P;Zhao D;Young M;Richard D;Liu Z;Emami A;Portilla G;Hosseinzadeh S;Cao J;Maridas D;Sedlak M;Menghini D;Cheng L;Li L;Ding X;Ding Y;Rosen V;Kiapour AM;Capellini TD
考虑到编码序列的多性性以及许多位点表现出多种疾病关联，在非编码序列中可能存在疾病特异性。在这里，我们专注于关节疾病，在复制的基因座中发现，GDF5表现出超过20种不同的关联，我们确定了其两个最强关联的因果变异，髋关节发育不良和膝关节骨关节炎。通过绘制关节软骨细胞的调控区域，我们确定了两个变体（rs4911178; rs6060369），它们存在于解剖位点特异性增强子中，具有相同的风险单倍型。我们发现这两种变异具有临床相关性，通过改变形态影响疾病。通过在人源化小鼠中模拟每种变体，我们观察到与GDF5表达相关的关节特异性反应。因此，我们在导致关节特异性疾病的常见风险单倍型上解耦单独的调节变异。通过拓宽我们的视角，我们最终发现GDF5的模块化模式也存在于超过四分之三的与多种GWAS疾病相关的基因座上。虽然已经发现许多基因位点与疾病有关，但对它们的因果变异和机制进行研究的并不多。在这里，作者通过实验解剖了GDF5附近的两个位点，这两个位点与两种不同的关节疾病相关，并映射到独立的调节元件。
Given the pleiotropic nature of coding sequences and that many loci exhibit multiple disease associations, it is within non-coding sequence that disease-specificity likely exists. Here, we focus on joint disorders, finding among replicated loci, that GDF5 exhibits over twenty distinct associations, and we identify causal variants for two of its strongest associations, hip dysplasia and knee osteoarthritis. By mapping regulatory regions in joint chondrocytes, we pinpoint two variants (rs4911178; rs6060369), on the same risk haplotype, which reside in anatomical site-specific enhancers. We show that both variants have clinical relevance, impacting disease by altering morphology. By modeling each variant in humanized mice, we observe joint-specific response, correlating with GDF5 expression. Thus, we uncouple separate regulatory variants on a common risk haplotype that cause joint-specific disease. By broadening our perspective, we finally find that patterns of modularity at GDF5 are also found at over three-quarters of loci with multiple GWAS disease associations. While many genetic loci have been found to be associated with disease, not many have had their causal variants and mechanisms investigated. Here, the authors experimentally dissect two loci near GDF5 which are associated with two different joint disorders and which map to independent regulatory elements.
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DOI：
10.1038/ejhg.2012.197
发表时间：
2013-05
期刊：
European journal of human genetics : EJHG
影响因子：
--
作者：
通讯作者：
--
通过 Bmp5 基因中的模块化调控元件塑造骨骼生长。
影响因子：
4.5
作者：
Guenther C;Pantalena-Filho L;Kingsley DM
通讯作者：
Kingsley DM
影响因子：
9.2
作者：
Chang CC;Chow CC;Tellier LC;Vattikuti S;Purcell SM;Lee JJ
通讯作者：
Lee JJ
影响因子：
14.9
作者：
Buniello, Annalisa;MacArthur, Jacqueline A. L.;Parkinson, Helen
通讯作者：
Parkinson, Helen
影响因子：
9.8
作者：
Browning, Brian L.;Zhou, Ying;Browning, Sharon R.
通讯作者：
Browning, Sharon R.