Abstract
BackgroundGenetic factors that influence kidney traits have been understudied for low frequency and ancestry-specific variants.MethodsWe 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.FindingsWhen 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.InterpretationThis study highlights challenges in studying variants influencing kidney traits that are low frequency in populations and more common in non-European ancestry.
Highlights
Reduced kidney function, assessed with the estimate glomerular filtration rate, defines chronic kidney disease (CKD)
The variants most significantly associated with estimated glomerular filtration rate (eGFR) were located on chromosomes 1, chromosome 2 and chromosome 19, were all rare and combined explained 0.5% of the trait variance (Table 1)
The variants significantly associated with eGFR on chromosomes 15 and 17 were previously reported [33]
Summary
Reduced kidney function, assessed with the estimate glomerular filtration rate (eGFR), defines chronic kidney disease (CKD). The current study expands on prior genetic studies of kidney loci through interrogation of rare and low frequency variants from whole genome sequencing (WGS) in the National Heart Lung and Blood Institute’s Trans-Omics for Precision Medicine (TOPMed) program. We aimed to understand a role of rare and low frequency variants that individually or in aggregate influence eGFR, and to identify ancestry-specific genomic regions associated with eGFR in African Americans and Hispanics/Latinos through admixture mapping. 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). Interpretation: This study highlights challenges in studying variants influencing kidney traits that are low frequency in populations and more common in non-European ancestry
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