Digital Engineering Faculty, University of Potsdam, Potsdam, Germany, Prof.-Dr.-Helmert-Str. 2-3, 14482.
Hasso Plattner Institute for Digital Health at Mount Sinai, Icahn School of Medicine at Mount Sinai, New York City, NY, USA.
Sci Rep. 2024 Apr 26;14(1):9642. doi: 10.1038/s41598-024-59747-4.
Chronic kidney disease (CKD) is a complex disorder that causes a gradual loss of kidney function, affecting approximately 9.1% of the world's population. Here, we use a soft-clustering algorithm to deconstruct its genetic heterogeneity. First, we selected 322 CKD-associated independent genetic variants from published genome-wide association studies (GWAS) and added association results for 229 traits from the GWAS catalog. We then applied nonnegative matrix factorization (NMF) to discover overlapping clusters of related traits and variants. We computed cluster-specific polygenic scores and validated each cluster with a phenome-wide association study (PheWAS) on the BioMe biobank (n = 31,701). NMF identified nine clusters that reflect different aspects of CKD, with the top-weighted traits signifying areas such as kidney function, type 2 diabetes (T2D), and body weight. For most clusters, the top-weighted traits were confirmed in the PheWAS analysis. Results were found to be more significant in the cross-ancestry analysis, although significant ancestry-specific associations were also identified. While all alleles were associated with a decreased kidney function, associations with CKD-related diseases (e.g., T2D) were found only for a smaller subset of variants and differed across genetic ancestry groups. Our findings leverage genetics to gain insights into the underlying biology of CKD and investigate population-specific associations.
慢性肾脏病（CKD）是一种复杂的疾病，会导致肾功能逐渐丧失，影响全球约 9.1%的人口。在这里，我们使用软聚类算法来分解其遗传异质性。首先，我们从已发表的全基因组关联研究（GWAS）中选择了 322 个与 CKD 相关的独立遗传变异，并添加了来自 GWAS 目录的 229 个特征的关联结果。然后，我们应用非负矩阵分解（NMF）来发现相关特征和变异的重叠聚类。我们计算了每个聚类的特异性多基因评分，并在 BioMe 生物库（n=31701）上进行了全表型关联研究（PheWAS）来验证每个聚类。NMF 确定了 9 个反映 CKD 不同方面的聚类，加权最高的特征代表了肾脏功能、2 型糖尿病（T2D）和体重等方面。对于大多数聚类，加权最高的特征在 PheWAS 分析中得到了确认。尽管也确定了具有显著遗传特异性的关联，但在跨种族分析中结果更为显著。虽然所有等位基因都与肾功能下降相关，但与 CKD 相关疾病（如 T2D）的关联仅在较小的变异子集上发现，并且在不同的遗传祖先群体中有所不同。我们的研究结果利用遗传学深入了解 CKD 的潜在生物学，并研究特定人群的关联。
