Association of Polygenic Risk Scores for Multiple Cancers in a Phenome-wide Study: Results from The Michigan Genomics Initiative
Association of Polygenic Risk Scores for Multiple Cancers in a Phenome-wide Study: Results from The Michigan Genomics Initiative
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DOI：
10.1016/j.ajhg.2018.04.001
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发表时间：
2018-06-07
影响因子：
9.8
通讯作者：
Mukherjee, Bhramar
中科院分区：
文献类型：
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作者：
Fritsche, Lars G.;Gruber, Stephen B.;Mukherjee, Bhramar
卫生系统是患者电子健康记录（EHR）数据的管理者，其深度和广度极其丰富，反映了数以千计的诊断和暴露情况。基因组变异的测量与电子病历相结合，提供了一种潜在的策略，可以准确地对患者进行风险分析，并发现诊断和基因组之间的新关系。本研究的目的是评估常见癌症的多基因风险评分（PRS）是否与多种表型相关，该研究在一项全表型关联研究（PheWAS）中进行，该研究对28,260名不相关的、基因分型的近期欧洲血统患者进行了研究，这些患者同意参加密歇根基因组学计划，这是密歇根医学的一项纵向生物存储工作。利用NHGRI-EBI目录中的汇总统计数据计算12个癌症性状的PRS。共1711项综合病例对照研究用于PheWAS分析。在本研究样本中，有13490例（47.7%）患者至少有一种癌症诊断。PRS与女性乳腺癌、前列腺癌、黑色素瘤、基底细胞癌、鳞状细胞癌和甲状腺癌等癌症特征有很强的相关性。在现象范围内观察到PRS与许多非癌症诊断之间的显著关联。为了区分由主要性状驱动的PRS关联和由共同遗传风险谱引起的关联，引入了“排除PRS PheWAS”的概念。对诊断时间顺序的进一步分析提高了我们对这些次要关联的理解。这个全面的PheWAS使用了PRS而不是单一的变体。
Health systems are stewards of patient electronic health record (EHR) data with extraordinarily rich depth and breadth, reflecting thousands of diagnoses and exposures. Measures of genomic variation integrated with EHRs offer a potential strategy to accurately stratify patients for risk profiling and discover new relationships between diagnoses and genomes. The objective of this study was to evaluate whether polygenic risk scores (PRS) for common cancers are associated with multiple phenotypes in a phenome-wide association study (PheWAS) conducted in 28,260 unrelated, genotyped patients of recent European ancestry who consented to participate in the Michigan Genomics Initiative, a longitudinal biorepository effort within Michigan Medicine. PRS for 12 cancer traits were calculated using summary statistics from the NHGRI-EBI catalog. A total of 1,711 synthetic case-control studies was used for PheWAS analyses. There were 13,490 (47.7%) patients with at least one cancer diagnosis in this study sample. PRS exhibited strong association for several cancer traits they were designed for, including female breast cancer, prostate cancer, melanoma, basal cell carcinoma, squamous cell carcinoma, and thyroid cancer. Phenome-wide significant associations were observed between PRS and many non-cancer diagnoses. To differentiate PRS associations driven by the primary trait from associations arising through shared genetic risk profiles, the idea of "exclusion PRS PheWAS'' was introduced. Further analysis of temporal order of the diagnoses improved our understanding of these secondary associations. This comprehensive PheWAS used PRS instead of a single variant.