Whole genome sequence analyses of eGFR in 23,732 people representing multiple ancestries in the NHLBI trans-omics for precision medicine (TOPMed) consortium

Background: Genetic factors that influence kidney traits have been understudied for low frequency and ancestry-specific variants. Methods: We combined whole genome sequencing (WGS) data from 23,732 participants from 10 NHLBI Trans-Omics for Precision Medicine (TOPMed) Program multi-ethnic studies to identify novel loci for estimated glomerular filtration rate (eGFR). Participants included European, African, East Asian, and Hispanic ancestries. We applied linear mixed models using a genetic relationship matrix estimated from the WGS data and adjusted for age, sex, study, and ethnicity. Findings: When testing single variants, we identified three novel loci driven by low frequency variants more commonly observed in non-European ancestry (PRKAA2, rs180996919, minor allele frequency [MAF] 0.04%, P = 6.1 × 10⁻¹¹; METTL8, rs116951054, MAF 0.09%, P = 4.5 × 10⁻⁹; and MATK, rs539182790, MAF 0.05%, P = 3.4 × 10⁻⁹). We also replicated two known loci for common variants (rs2461702, MAF=0.49, P = 1.2 × 10⁻⁹, nearest gene GATM, and rs71147340, MAF=0.34, P = 3.3 × 10⁻⁹, CDK12). Testing aggregated variants within a gene identified the MAF gene. A statistical approach based on local ancestry helped to identify replication samples for ancestry-specific variants. Interpretation: This study highlights challenges in studying variants influencing kidney traits that are low frequency in populations and more common in non-European ancestry.