Department of Genetics, School of Medicine, Stanford University, Stanford, CA, USA.
Institute for Molecular Medicine Finland, FIMM, HiLIFE, University of Helsinki, Helsinki, Finland.
Nat Genet. 2021 Feb;53(2):185-194. doi: 10.1038/s41588-020-00757-z. Epub 2021 Jan 18.
Clinical laboratory tests are a critical component of the continuum of care. We evaluate the genetic basis of 35 blood and urine laboratory measurements in the UK Biobank (n = 363,228 individuals). We identify 1,857 loci associated with at least one trait, containing 3,374 fine-mapped associations and additional sets of large-effect (>0.1 s.d.) protein-altering, human leukocyte antigen (HLA) and copy number variant (CNV) associations. Through Mendelian randomization (MR) analysis, we discover 51 causal relationships, including previously known agonistic effects of urate on gout and cystatin C on stroke. Finally, we develop polygenic risk scores (PRSs) for each biomarker and build 'multi-PRS' models for diseases using 35 PRSs simultaneously, which improved chronic kidney disease, type 2 diabetes, gout and alcoholic cirrhosis genetic risk stratification in an independent dataset (FinnGen; n = 135,500) relative to single-disease PRSs. Together, our results delineate the genetic basis of biomarkers and their causal influences on diseases and improve genetic risk stratification for common diseases.
临床实验室检测是连续护理的重要组成部分。我们在英国生物银行（n=363228 人）中评估了 35 项血液和尿液实验室测量的遗传基础。我们确定了 1857 个与至少一个特征相关的基因座，其中包含 3374 个精细映射的关联和其他一些大效应（>0.1 个标准差）的蛋白质改变、人类白细胞抗原（HLA）和拷贝数变异（CNV）关联。通过孟德尔随机化（MR）分析，我们发现了 51 个因果关系，包括尿酸对痛风和胱抑素 C 对中风的先前已知的激动作用。最后，我们为每个生物标志物开发了多基因风险评分（PRS），并使用 35 个 PRS 同时为疾病构建“多-PRS”模型，这在独立数据集（FinnGen；n=135500）中提高了慢性肾病、2 型糖尿病、痛风和酒精性肝硬化的遗传风险分层，相对于单一疾病 PRS。总之，我们的研究结果描绘了生物标志物的遗传基础及其对疾病的因果影响，并改善了常见疾病的遗传风险分层。
