Biomedical Laboratory Research and Development, Tennessee Valley Healthcare System (626)/Vanderbilt University, Nashville, TN, USA.
Division of Genetic Medicine, Department of Medicine, Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN, USA.
Nat Commun. 2019 Aug 26;10(1):3842. doi: 10.1038/s41467-019-11704-w.
Chronic kidney disease (CKD), defined by low estimated glomerular filtration rate (eGFR), contributes to global morbidity and mortality. Here we conduct a transethnic Genome-Wide Association Study of eGFR in 280,722 participants of the Million Veteran Program (MVP), with replication in 765,289 participants from the Chronic Kidney Disease Genetics (CKDGen) Consortium. We identify 82 previously unreported variants, confirm 54 loci, and report interesting findings including association of the sickle cell allele of betaglobin among non-Hispanic blacks. Our transcriptome-wide association study of kidney function in healthy kidney tissue identifies 36 previously unreported and nine known genes, and maps gene expression to renal cell types. In a Phenome-Wide Association Study in 192,868 MVP participants using a weighted genetic score we detect associations with CKD stages and complications and kidney stones. This investigation reinterprets the genetic architecture of kidney function to identify the gene, tissue, and anatomical context of renal homeostasis and the clinical consequences of dysregulation.
慢性肾脏病（CKD）定义为肾小球滤过率（eGFR）降低，导致全球发病率和死亡率上升。本研究对百万退伍军人计划（MVP）中的 280722 名参与者进行了跨种族全基因组关联研究，在慢性肾脏病遗传学（CKDGen）联盟的 765289 名参与者中进行了复制。我们鉴定出 82 个以前未报道的变异，确认了 54 个基因座，并报告了一些有趣的发现，包括非西班牙裔黑人群体中β球蛋白的镰状细胞等位基因与 eGFR 的关联。我们对健康肾脏组织中肾功能的全转录组关联研究鉴定出 36 个以前未报道的和 9 个已知基因，并将基因表达映射到肾细胞类型。在 MVP 中进行的 192868 名参与者的表型全基因组关联研究中，我们使用加权遗传评分检测到与 CKD 分期和并发症以及肾结石的关联。这项研究重新解释了肾功能的遗传结构，以确定肾脏内稳态的基因、组织和解剖背景以及失调的临床后果。
