Combination of mouse models and genomewide association studies highlights novel genes associated with human kidney function.
Combination of mouse models and genomewide association studies highlights novel genes associated with human kidney function.
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DOI：
10.1016/j.kint.2016.04.004
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发表时间：
2016-10
影响因子：
19.6
通讯作者：
Jiaojiao Jing;C. Pattaro;Anselm Hoppmann;Y. Okada;C. Fox;A. Köttgen
中科院分区：
文献类型：
--
作者：
Jiaojiao Jing;C. Pattaro;Anselm Hoppmann;Y. Okada;C. Fox;A. Köttgen
全基因组关联研究已经确定了许多慢性肾脏疾病相关的遗传变异，但往往不能确定致病基因。通过将小鼠基因组信息学与人类肾功能全基因组关联研究相结合，解决了这一限制。小鼠模型显示肾脏生理、形态、肾小球滤过率（GFR）或尿白蛋白/肌酐比异常的基因从小鼠基因组信息学中鉴定。随后，在CKDGen联盟的全基因组关联研究荟萃分析中，对133814名个体的gfr相关单核苷酸多态性和54451名个体的尿白蛋白-肌酐比值相关snp进行了相应的人类同源物评估。经过多次测试修正，分别在小鼠中鉴定出2、7和17个基因的单核苷酸多态性与估计的GFR有显著关联，导致GFR异常、生理异常和形态异常。肾脏形态异常的基因显示gfr相关单核苷酸多态性显著富集。总共有19个基因包含与估计的GFR或尿白蛋白与肌酐比值相关的变异，其中16个映射到先前报道的全基因组显著位点。cyp26a1和bmp4作为新信号出现，随后在一项大型独立研究中得到证实。一个额外的基因CYP24A1，是在对附近公布的关联信号进行调节后发现的。因此，我们将综合小鼠表型信息与人类全基因组关联研究数据相结合的新方法导致了肾脏疾病发病机制候选基因的鉴定。
Genomewide association studies have identified numerous chronic kidney disease–associated genetic variants, but often do not pinpoint causal genes. This limitation was addressed by combining Mouse Genome Informatics with human genomewide association studies of kidney function. Genes for which mouse models showed abnormal renal physiology, morphology, glomerular filtration rate (GFR), or urinary albumin-to-creatinine ratio were identified from Mouse Genome Informatics. The corresponding human orthologs were then evaluated for GFR-associated single-nucleotide polymorphisms in 133,814 individuals and urinary albumin-to-creatinine ratio-associated SNPs in 54,451 individuals in genome-wide association studies meta-analysis of the CKDGen Consortium. After multiple testing corrections, significant associations with estimated GFR in humans were identified for single-nucleotide polymorphisms in 2, 7, and 17 genes causing abnormal GFR, abnormal physiology, and abnormal morphology in mice, respectively. Genes identified for abnormal kidney morphology showed significant enrichment for estimated GFR–associated single-nucleotide polymorphisms. In total, 19 genes contained variants associated with estimated GFR or the urinary albumin-to-creatinine ratio of which 16 mapped into previously reported genomewide significant loci.CYP26A1andBMP4emerged as novel signals subsequently validated in a large, independent study. An additional gene,CYP24A1, was discovered after conditioning on a published nearby association signal. Thus, our novel approach to combine comprehensive mouse phenotype information with human genomewide association studies data resulted in the identification of candidate genes for kidney disease pathogenesis.