Genetic insights into ossification of the posterior longitudinal ligament of the spine-猫眼课题宝

DOI：

10.1101/2022.06.16.22276152

发表时间：

2022-06

期刊：

eLife

影响因子：

7.7

通讯作者：

中科院分区：

生物学1区

文献类型：

作者：

Y. Koike;M. Takahata;M. Nakajima;N. Otomo;H. Suetsugu;X. Liu;T. Endo;S. Imagama;K. Kobayashi;T. Kaito;S. Kato;Y. Kawaguchi;M. Kanayama;H. Sakai;T. Tsuji;T. Miyamoto;H. Inose;T. Yoshii;M. Kashii;H. Nakashima;K. Ando;Y. Taniguchi;K. Takeuchi;S. Ito;K. Tomizuka;K. Hikino;Y. Iwasaki;Y. Kamatani;S. Maeda;H. Nakajima;K. Mori;A. Seichi;S. Fujibayashi;T. Kanchiku;K. Watanabe;T. Tanaka;K. Kida;S. Kobayashi;M. Takahashi;K. Yamada;H. Takuwa;H. Lu;S. Niida;K. Ozaki;Y. Momozawa;Genetic Study Group of Investigation

背景：脊柱后纵韧带骨化（OPLL）是一种难治性疾病，会导致严重的神经功能缺损。其病因和发病机制大多未知。 OPLL与合并症尤其是2型糖尿病（T2D）和体重指数（BMI）之间的关系一直是人们关注的焦点；方法：为了阐明 OPLL 的病因和发病机制，我们对 22,016 名日本人进行了全基因组关联研究 (GAWS) 的荟萃分析。我们将OPLL分为颈椎型、胸椎型和其他类型，并进行了GWAS亚分析。我们进行了基于基因的关联分析和全转录组孟德尔随机化方法，以识别其他潜在的因果基因。为了研究与 OPLL 相关的细胞群，我们进行了细胞类型群富集分析。为了确定对 OPLL 具有因果影响的性状，我们评估了 99 个复杂性状的遗传相关性，然后进行了孟德尔随机化 (MR) 分析。最后，我们生成了多基因风险评分 (PRS)，以研究因果性状对 OPLL 亚型的遗传影响。结果：GWAS 荟萃分析确定了 14 个显着基因座，包括 8 个新基因座。 GWAS 子分析确定了亚型特异性信号。基于基因的关联分析和全转录组孟德尔随机化方法分别确定了五个和三个潜在的因果基因。这些基因座/基因包含骨代谢相关基因。细胞类型组富集分析观察到结缔/骨细胞组活性增强子中的多基因信号显着富集，特别是软骨分化细胞中的H3K27ac。遗传相关性与T2D和BMI呈正相关，与脑动脉瘤和骨质疏松呈负相关。 MR 分析表明，BMI 增加和骨矿物质密度 (BMD) 高对 OPLL 具有显着因果效应，但对 T2D 没有显着因果效应，表明高 BMI 混淆了 T2D 相关性。 BMI 的 PRS 表明 BMI 对胸部 OPLL 的影响尤其强烈。结论：我们确定了多个与骨代谢有关的致病基因，这些基因是未来治疗靶点的候选基因。通过 MR 分析，我们首次证明了常见代谢状况（高 BMI 和 BMD）与 OPLL 之间的因果关系。我们成功地将可干预特征与后纵韧带骨化联系起来。

Background: Ossification of the posterior longitudinal ligament of the spine (OPLL) is an intractable disease, leading to severe neurological deficits. Its etiology and pathogenesis are mostly unknown. The relationship between OPLL and comorbidities, especially type 2 diabetes (T2D) and body mass index (BMI), has been the focus of attention; however, no trait has been proven to have a causal relationship.Methods: To clarify the etiology and pathogenesis of OPLL, we conducted a meta-analysis of genome-wide association studies (GAWSs) using 22,016 Japanese individuals. We classified OPLL into cervical, thoracic and the other types, and conducted GWAS sub-analyses. We conducted a gene-based association analysis and a transcriptome-wide Mendelian randomization approach to identify other potential causal genes. To investigate cell groups related to OPLL, we conducted cell type group enrichment analysis. To identify traits with a causal effect on OPLL, we evaluated the genetic correlation with 99 complex traits and then performed mendelian randomization (MR) analyses. Finally, we generated polygenic risk score (PRS) to investigate the genetic impact of the causal trait on OPLL subtypes.Results: A GWAS meta-analysis identified 14 significant loci, including eight novel loci. GWAS sub-analyses identified subtype-specific signals. A Gene-based association analysis and a transcriptome-wide Mendelian randomization approach identified five and three potential causal genes, respectively. These loci/genes contained bone metabolism-related genes. Cell type group enrichment analysis observed significant enrichment of the polygenic signals in the active enhancers of the connective/bone cell group, especially H3K27ac in chondrogenic differentiation cells. Genetic correlations showed positive correlation with T2D and BMI and negative correlation with cerebral aneurysm and osteoporosis. MR analysesdemonstrated a significant causal effect of increased BMI and high bone mineral density (BMD) on OPLL, but not of T2D, indicating that high BMI confounded the T2D correlation. A PRS for BMI demonstrated that the effect of BMI wasparticularly strong in thoracic OPLL.Conclusion: We identified multiple causative genes involved in bone metabolism that are candidates for future therapeutic targets. By MR analyses, we showed for the first time a causal relationship between the common metabolic conditions (high BMI and BMD) and OPLL. We successfully linked intervenable traits to OPLL.

Genetic insights into ossification of the posterior longitudinal ligament of the spine

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