Discovering Novel Loci of Chronic Kidney Disease via Principal Component Analysis-Based Multiple-Trait Genome-Wide Association Study

Introduction: Chronic kidney diseases (CKD) encompass a spectrum of complex pathophysiological processes. While numerous genome-wide association studies (GWASs) have focused on individual traits such as albuminuria, estimated glomerular filtration rate (eGFR), and eGFR change, there remains a paucity of genetic studies integrating these traits collectively for comprehensive evaluation.

Methods: In this study, we performed individual GWASs for albuminuria, baseline eGFR, and eGFR slope utilizing data from non-diabetic individuals enrolled from the Taiwan Biobank (TWB). Subsequently, we employed principal component analysis to transform these three quantitative traits into principal components (PCs) and performed GWAS based on these principal components (PC-based GWAS).

Results: The individual GWAS analyses of albuminuria, baseline eGFR, and eGFR slope identified 10, 13, and 210 candidate loci respectively, with 2, 3, and 99 of them representing previously reported loci. PC-based GWAS identified additional 20 novel candidate loci linked to CKD (p values ranging from 5.8 × 10-7 to 9.1 × 10-6). Notably, 4 of these 20 single nucleotide polymorphisms (rs9332641, rs10737429, rs117231653, and rs73360624) exhibited significant associations with kidney expression quantitative trait loci.

Conclusion: To our knowledge, this study represents the first PC-based GWAS integrating albuminuria, baseline eGFR, and eGFR slope. Our approach found 20 novel candidate loci suggestively associated with CKD, underscoring the value of integrating multiple kidney traits in unraveling the pathophysiology of this complex disorder.