Trans-Ethnic Polygenic Analysis Supports Genetic Overlaps of Lumbar Disc Degeneration With Height, Body Mass Index, and Bone Mineral Density.
Trans-Ethnic Polygenic Analysis Supports Genetic Overlaps of Lumbar Disc Degeneration With Height, Body Mass Index, and Bone Mineral Density.
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DOI：
10.3389/fgene.2018.00267
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发表时间：
2018
影响因子：
3.7
通讯作者：
Sham PC
中科院分区：
文献类型：
--
作者：
Zhou X;Cheung CL;Karasugi T;Karppinen J;Samartzis D;Hsu YH;Mak TS;Song YQ;Chiba K;Kawaguchi Y;Li Y;Chan D;Cheung KM;Ikegawa S;Cheah KS;Sham PC
腰椎间盘退行性变(LDD)是与年龄相关的腰椎间纤维软骨关节的破坏。它是腰痛的一个主要原因，通常通过磁共振成像(MRI)进行评估。与大多数其他复杂性状一样，LDD可能是多基因的，受遗传和环境因素的影响。然而，由于样本量有限，LDD的全基因组关联研究(GWAS)发现的易感基因位点很少。以往的流行病学研究也报道了多种可遗传的危险因素，包括身高、体重指数(BMI)、骨密度(BMD)、血脂水平等。遗传学可以帮助阐明性状之间的因果关系，并提示具有多效性的基因座。一种这样的方法是多基因评分(PGS)，它通过由GWAS估计的影响加权的等位基因的总和来总结多个变异的影响。为了研究腰椎间盘突出症和相关遗传危险因素的遗传重叠，我们计算了中国人群中身高、BMI、BMD和血脂水平的PGS，包括脊柱MRI检查和日本腰椎间盘突出症(LDH)需要手术的病例对照队列。因为大多数大规模的GWAS是在欧洲群体中进行的，所以相应性状的PG是使用来自欧洲GWAS的权重创建的。我们在独立的中国样本中校准了它们的预测性能，然后测试了与MRI得出的LDD评分和LDH影响状态的相关性。中国人的身高、BMI、BMD和血脂水平的PGS与各自的表型密切相关，但所解释的表型变异低于欧洲人，这将降低检测遗传重叠的能力。尽管如此，BMI的PGS和腰椎BMD与LDD评分显著相关；身高的PGS与LDH的易感性增加相关。此外，连锁不平衡得分回归表明，骨关节炎，另一种与LDD有共同特征的退行性疾病，也与身高、BMI和BMD显示出遗传相关性。这些发现提示生物力学应力在LDD发病机制中的共同关键作用，并将指导未来对多效性基因的寻找。
Lumbar disc degeneration (LDD) is age-related break-down in the fibrocartilaginous joints between lumbar vertebrae. It is a major cause of low back pain and is conventionally assessed by magnetic resonance imaging (MRI). Like most other complex traits, LDD is likely polygenic and influenced by both genetic and environmental factors. However, genome-wide association studies (GWASs) of LDD have uncovered few susceptibility loci due to the limited sample size. Previous epidemiology studies of LDD also reported multiple heritable risk factors, including height, body mass index (BMI), bone mineral density (BMD), lipid levels, etc. Genetics can help elucidate causality between traits and suggest loci with pleiotropic effects. One such approach is polygenic score (PGS) which summarizes the effect of multiple variants by the summation of alleles weighted by estimated effects from GWAS. To investigate genetic overlaps of LDD and related heritable risk factors, we calculated the PGS of height, BMI, BMD and lipid levels in a Chinese population-based cohort with spine MRI examination and a Japanese case-control cohort of lumbar disc herniation (LDH) requiring surgery. Because most large-scale GWASs were done in European populations, PGS of corresponding traits were created using weights from European GWASs. We calibrated their prediction performance in independent Chinese samples, then tested associations with MRI-derived LDD scores and LDH affection status. The PGS of height, BMI, BMD and lipid levels were strongly associated with respective phenotypes in Chinese, but phenotype variances explained were lower than in Europeans which would reduce the power to detect genetic overlaps. Despite of this, the PGS of BMI and lumbar spine BMD were significantly associated with LDD scores; and the PGS of height was associated with the increased the liability of LDH. Furthermore, linkage disequilibrium score regression suggested that, osteoarthritis, another degenerative disorder that shares common features with LDD, also showed genetic correlations with height, BMI and BMD. The findings suggest a common key contribution of biomechanical stress to the pathogenesis of LDD and will direct the future search for pleiotropic genes.