Journal Article

Discovery of genomic and transcriptomic pleiotropy between kidney function and soluble receptor for advanced glycation end products using correlated meta‐analyses: The Long Life Family Study

Kuipers, Allison L., Acharya, Sandeep, Lin, Shiow J., Brent, Michael R., Thyagarajan, Bharat, Province, Michael A., Kulminski, Alexander, Zmuda, Joseph M., Wojczynski, Mary K., Feitosa, Mary F., Christensen, Kaare

2024

Overview

Patients with chronic kidney disease (CKD) have increased oxidative stress and chronic inflammation, which may escalate the production of advanced glycation end‐products (AGEs). High soluble receptor for AGE (sRAGE) and low estimated glomerular filtration rate (eGFR) levels are associated with CKD and aging. We evaluated whether eGFR calculated from creatinine and cystatin C share pleiotropic genetic factors with sRAGE. We employed whole‐genome sequencing and correlated meta‐analyses on combined genome‐wide association study (GWAS) p‐values in 4182 individuals (age range: 24–110) from the Long Life Family Study (LLFS). We also conducted transcriptome‐wide association studies (TWAS) on whole blood in a subset of 1209 individuals. We identified 59 pleiotropic GWAS loci (p < 5 × 10−8) and 17 TWAS genes (Bonferroni‐p < 2.73 × 10−6) for eGFR traits and sRAGE. TWAS genes, LSP1 and MIR23AHG, were associated with eGFR and sRAGE located within GWAS loci, lncRNA‐KCNQ1OT1 and CACNA1A/CCDC130, respectively. GWAS variants were eQTLs in the kidney glomeruli and tubules, and GWAS genes predicted kidney carcinoma. TWAS genes harbored eQTLs in the kidney, predicted kidney carcinoma, and connected enhancer‐promoter variants with kidney function‐related phenotypes at p < 5 × 10−8. Additionally, higher allele frequencies of protective variants for eGFR traits were detected in LLFS than in ALFA‐Europeans and TOPMed, suggesting better kidney function in healthy‐aging LLFS than in general populations. Integrating genomic annotation and transcriptional gene activity revealed the enrichment of genetic elements in kidney function and aging‐related processes. The identified pleiotropic loci and gene expressions for eGFR and sRAGE suggest their underlying shared genetic effects and highlight their roles in kidney‐ and aging‐related signaling pathways. Our study, conducted through correlated meta‐analysis in the Long Life Family Study, which recruited participants in the upper generation with exceptional family longevity, identified 42 novel pleiotropic GWAS loci in 4182 individuals with whole‐genome sequencing, and 17 TWAS genes for eGFRcr, eGFRcys, and sRAGE. The identified loci and genes suggest their underlying shared genetic and functional regulatory effects and highlight their roles in kidney‐ and aging‐related signaling pathways.

• Publisher: John Wiley & Sons, Inc,John Wiley and Sons Inc
• Subject: Advanced glycosylation end products / Age / Aging / Biomarkers / Carcinoma / Chronic illnesses / chronic kidney disease / Creatinine / Cystatin C / Diabetes / eGFR / Epidermal growth factor receptors / functional genome annotations / Gene frequency / Genes / Genetic analysis / Genetic factors / Genome-wide association studies / Genomes / genome‐wide association study / Genomics / Genotype & phenotype / Glomerular filtration rate / Glomerulus / Inflammation / KCNQ1OT1 protein / Kidney diseases / Meta-analysis / Mortality / Older people / omics / Oxidative stress / Phenotypes / Pleiotropy / Population genetics / Potassium channels (voltage-gated) / sRAGE / Transcriptomes / transcriptome‐wide association study / Transcriptomics / Tubules / Whole genome sequencing