Division of Genetic Epidemiology, Institute for Medical Biometry and Statistics, Faculty of Medicine, and Medical Centre - University of Freiburg, Berliner Allee 29, 79110 Freiburg, Germany.
Department of Medicine IV, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Hugstetter Str. 55, 79106 Freiburg, Germany.
Nat Rev Nephrol. 2016 Sep;12(9):549-62. doi: 10.1038/nrneph.2016.107. Epub 2016 Aug 1.
Over the past decade, genome-wide association studies (GWAS) have considerably improved our understanding of the genetic basis of kidney function and disease. Population-based studies, used to investigate traits that define chronic kidney disease (CKD), have identified >50 genomic regions in which common genetic variants associate with estimated glomerular filtration rate or urinary albumin-to-creatinine ratio. Case-control studies, used to study specific CKD aetiologies, have yielded risk loci for specific kidney diseases such as IgA nephropathy and membranous nephropathy. In this Review, we summarize important findings from GWAS and clinical and experimental follow-up studies. We also compare risk allele frequency, effect sizes, and specificity in GWAS of CKD-defining traits and GWAS of specific CKD aetiologies and the implications for study design. Genomic regions identified in GWAS of CKD-defining traits can contain causal genes for monogenic kidney diseases. Population-based research on kidney function traits can therefore generate insights into more severe forms of kidney diseases. Experimental follow-up studies have begun to identify causal genes and variants, which are potential therapeutic targets, and suggest mechanisms underlying the high allele frequency of causal variants. GWAS are thus a useful approach to advance knowledge in nephrology.
在过去的十年中，全基因组关联研究（GWAS）极大地提高了我们对肾功能和疾病遗传基础的理解。用于研究定义慢性肾脏病（CKD）的特征的基于人群的研究已经确定了>50 个与估计肾小球滤过率或尿白蛋白与肌酐比值相关的常见遗传变异的基因组区域。用于研究特定 CKD 病因的病例对照研究已经产生了特定肾脏疾病（如 IgA 肾病和膜性肾病）的风险基因座。在这篇综述中，我们总结了 GWAS 以及临床和实验随访研究的重要发现。我们还比较了 CKD 定义特征的 GWAS 和特定 CKD 病因的 GWAS 中风险等位基因频率、效应大小和特异性，以及对研究设计的影响。在 CKD 定义特征的 GWAS 中确定的基因组区域可能包含单基因肾脏疾病的因果基因。因此，对肾脏功能特征的基于人群的研究可以深入了解更严重形式的肾脏疾病。实验随访研究已经开始确定潜在的治疗靶点的因果基因和变体，并提出了因果变体高频的潜在机制。因此，GWAS 是推进肾脏病学知识的有用方法。
