Genome-wide polygenic risk score for major osteoporotic fractures in postmenopausal women using associated single nucleotide polymorphisms.
Genome-wide polygenic risk score for major osteoporotic fractures in postmenopausal women using associated single nucleotide polymorphisms.
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DOI：
10.1186/s12967-023-03974-2
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发表时间：
2023-02-16
影响因子：
7.4
通讯作者：
Jung, Jongyun
中科院分区：
文献类型：
--
作者：
Wu, Qing;Jung, Jongyun
骨质疏松症是高度多基因和遗传性的，遗传率范围为50%至80%;大多数遗传易感性与许多常见遗传变异的累积效应有关。然而，现有的遗传风险评分（GRS）仅提供了百分之几的预测能力，骨质疏松性骨折。我们推导并验证了一种新的全基因组多基因评分（GPS），包括103，155种常见的遗传变异，以量化这种易感性，并在一个独立的数据集（n = 15，776）中测试了这种GPS预测能力。在绝经后妇女中，我们发现在GPS十分位数中，严重骨质疏松性骨折（MOF）的风险增加了5倍（p < 0.001），严重骨质疏松的风险增加了15.25倍（p < 0.001）。与GPS分布的其余部分相比，顶部GPS十分位数与任何骨折、MOF、髋部骨折和脊柱骨折的风险分别增加3.59、2.48、1.92和1.58倍相关。基于1103个条件独立的全基因组显著性SNP，GPS前十分位也比传统GRS前十分位识别出近两倍的高风险阿尔茨海默病患者。尽管50岁左右的绝经后妇女发生严重骨质疏松症的相对风险相对相似，但在20年随访时，GPS最高十分位数（13.7%）和最低十分位数（< 1%）之间的累积发生率存在显著差异。在亚组分析中，非西班牙裔白色人群的GPS可转移性优于其他人种/种族人群。这种新的方法来量化遗传易感性骨质疏松症和骨质疏松性骨折提供了新的机会，临床预防和风险评估。在线版本包含补充材料，可通过10.1186/s12967-023-03974-2获得。
Osteoporosis is highly polygenic and heritable, with heritability ranging from 50 to 80%; most inherited susceptibility is associated with the cumulative effect of many common genetic variants. However, existing genetic risk scores (GRS) only provide a few percent predictive power for osteoporotic fracture. We derived and validated a novel genome-wide polygenic score (GPS) comprised of 103,155 common genetic variants to quantify this susceptibility and tested this GPS prediction ability in an independent dataset (n = 15,776). Among postmenopausal women, we found a fivefold gradient in the risk of major osteoporotic fracture (MOF) (p < 0.001) and a 15.25-fold increased risk of severe osteoporosis (p < 0.001) across the GPS deciles. Compared with the remainder of the GPS distribution, the top GPS decile was associated with a 3.59-, 2.48-, 1.92-, and 1.58-fold increased risk of any fracture, MOF, hip fracture, and spine fracture, respectively. The top GPS decile also identified nearly twofold more high-risk osteoporotic patients than the top decile of conventional GRS based on 1103 conditionally independent genome-wide significant SNPs. Although the relative risk of severe osteoporosis for postmenopausal women at around 50 is relatively similar, the cumulative incident at 20-year follow-up is significantly different between the top GPS decile (13.7%) and the bottom decile (< 1%). In the subgroup analysis, the GPS transferability in non-Hispanic White is better than in other racial/ethnic groups. This new method to quantify inherited susceptibility to osteoporosis and osteoporotic fracture affords new opportunities for clinical prevention and risk assessment. The online version contains supplementary material available at 10.1186/s12967-023-03974-2.
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影响因子：
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