Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
Center for Precision Psychiatry, Massachusetts General Hospital, Boston, MA, USA.
Genome Med. 2022 Jun 29;14(1):70. doi: 10.1186/s13073-022-01074-2.
Type 2 diabetes (T2D) is a worldwide scourge caused by both genetic and environmental risk factors that disproportionately afflicts communities of color. Leveraging existing large-scale genome-wide association studies (GWAS), polygenic risk scores (PRS) have shown promise to complement established clinical risk factors and intervention paradigms, and improve early diagnosis and prevention of T2D. However, to date, T2D PRS have been most widely developed and validated in individuals of European descent. Comprehensive assessment of T2D PRS in non-European populations is critical for equitable deployment of PRS to clinical practice that benefits global populations.
We integrated T2D GWAS in European, African, and East Asian populations to construct a trans-ancestry T2D PRS using a newly developed Bayesian polygenic modeling method, and assessed the prediction accuracy of the PRS in the multi-ethnic Electronic Medical Records and Genomics (eMERGE) study (11,945 cases; 57,694 controls), four Black cohorts (5137 cases; 9657 controls), and the Taiwan Biobank (4570 cases; 84,996 controls). We additionally evaluated a post hoc ancestry adjustment method that can express the polygenic risk on the same scale across ancestrally diverse individuals and facilitate the clinical implementation of the PRS in prospective cohorts.
The trans-ancestry PRS was significantly associated with T2D status across the ancestral groups examined. The top 2% of the PRS distribution can identify individuals with an approximately 2.5-4.5-fold of increase in T2D risk, which corresponds to the increased risk of T2D for first-degree relatives. The post hoc ancestry adjustment method eliminated major distributional differences in the PRS across ancestries without compromising its predictive performance.
By integrating T2D GWAS from multiple populations, we developed and validated a trans-ancestry PRS, and demonstrated its potential as a meaningful index of risk among diverse patients in clinical settings. Our efforts represent the first step towards the implementation of the T2D PRS into routine healthcare.
2 型糖尿病（T2D）是一种由遗传和环境风险因素共同导致的全球性疾病，它不成比例地影响着有色人种社区。利用现有的大规模全基因组关联研究（GWAS），多基因风险评分（PRS）已显示出补充已建立的临床风险因素和干预模式的潜力，并改善 T2D 的早期诊断和预防。然而，迄今为止，T2D PRS 主要在欧洲血统个体中得到了最广泛的开发和验证。全面评估非欧洲人群中的 T2D PRS 对于将 PRS 公平地应用于临床实践以造福全球人群至关重要。
我们整合了欧洲、非洲和东亚人群中的 T2D GWAS，使用新开发的贝叶斯多基因建模方法构建了跨种族 T2D PRS，并在多民族电子病历和基因组学（eMERGE）研究（11945 例病例；57694 例对照）、四个黑人队列（5137 例病例；9657 例对照）和台湾生物库（4570 例病例；84996 例对照）中评估了 PRS 的预测准确性。我们还评估了一种事后祖先调整方法，该方法可以在不同祖先的个体之间以相同的尺度表达多基因风险，并促进 PRS 在前瞻性队列中的临床实施。
跨种族 PRS 与所检查的祖先群体中的 T2D 状态显著相关。PRS 分布的前 2%可识别出 T2D 风险增加约 2.5-4.5 倍的个体，这与一级亲属的 T2D 风险增加相对应。事后祖先调整方法消除了 PRS 在不同祖源之间的主要分布差异，而不影响其预测性能。
通过整合来自多个群体的 T2D GWAS，我们开发并验证了一种跨种族 PRS，并证明了其在临床环境中作为不同患者风险的有意义指标的潜力。我们的努力代表了将 T2D PRS 纳入常规医疗保健的第一步。
Zotero 插件
