A Multi-Phenotype Approach Implicates SH2B3 in the Genetics of Chronic Kidney Disease

Chronic kidney disease (CKD) is a complex condition with diverse underlying causes that lead to a progressive decline in kidney function. Genome-wide association studies (GWASs) have identified numerous genetic loci associated with CKD, yet much of the genetic basis remains unexplained. Part of the reason is that most GWASs have only assessed kidney function via single biomarkers such as estimated glomerular filtration rate (eGFR). This study employs a novel multi-phenotype approach, combinatorial Principal Component Analysis (cPCA), to better understand the genetic architecture of CKD. Utilizing a discovery cohort of white British individuals from the UK Biobank (n=337,112), we analyzed 21 CKD-related phenotypes using cPCA to generate over 2 million composite phenotypes (CPs). More than 46,000 CPs demonstrated superior performance in classifying clinical CKD compared to any single biomarker, and those CPs were most frequently comprised of eGFR, cystatin C, HbA1c, microalbuminuria, albumin, and LDL. GWASs of the top 1,000 CPs revealed seven novel genetic loci, with CST3 and SH2B3 successfully replicated in an independent Irish cohort (n=11,106). Notably, the index SNP of the SH2B3 gene, which encodes a regulator in immune responses and cytokine signaling, is a loss-of-function variant with a combined beta of -0.046 and a p-value of 3.1E-56. These results highlight the effectiveness of a multi-phenotype approach in GWASs and implicate a novel functional variant in SH2B3 in CKD phenotypes. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement NKT has been supported by a QUT postgraduate scholarship. AJM has been supported by a Queensland Health Advancing Clinical Research Fellowship. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: This research has been conducted using the UK Biobank Resource under Application Number 60111. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes The summary statistics are publicly available in Figshare repository at https://doi.org/10.6084/m9.figshare.26122540.v1.