Longitudinal GWAS meta-analyses in >330,000 individuals identify new genetic loci for annual kidney function decline and large subgroup effects

Estimated glomerular filtration rate (eGFR) measures kidney function and eGFR decline can lead to kidney failure, necessitating dialysis or transplantation. Hundreds of genetic loci identified by genome-wide association studies (GWAS) for eGFR help explain population variability at a given point in time. However, the contribution of these or other loci to eGFR decline remain largely unknown and approaches to longitudinal GWAS underexplored. We present the first large-scale GWAS meta-analysis on annual eGFR decline (62 studies, n=343,339). Additional to the known positive control UMOD, we identified genome-wide significant, robust association for 7 loci unrelated to eGFR decline before, most of which independently supported by variant-by-age interaction (~350,000 individuals). Effects for eGFR decline were two- to four-fold larger among high-risk subgroups. Our results provide a first catalogue of genetics for kidney function decline and CKD progression, key to identify individuals at-risk and therapeutic targets, and a generally applicable framework for longitudinal GWAS.