Genetics of kidney traits in worldwide populations: the Continental Origins and Genetic Epidemiology Network (COGENT) Kidney Consortium

Abstract

We describe our collaborative efforts to increase representation of diverse populations in genomic research of kidney phenotypes to fill an unmet need to further understanding of the genetic contribution to chronic kidney disease (CKD) across the globe. These efforts led to the creation of the Continental Origins and Genetic Epidemiology Network Kidney (COGENT-Kidney) Consortium, focused on developing statistical methods for the analysis of genome-wide association studies (GWAS) across diverse populations and their application to renal traits and CKD. Resources generated within the consortium will provide a framework for future studies of genetic risk of CKD in worldwide populations. Our intent is to foster collaborations for studies of populations that are underrepresented in GWAS, increase awareness of the challenges and opportunities in studying these populations, and promote more genomic research across increasingly diverse populations.

Keywords: chronic kidney disease; diverse populations; gene expression.

Figure 1. Mendelian randomization to assess causal effects of eGFR on CKD and cause-specific kidney disease.

We performed Mendelian randomization to assess the causal association between eGFR and clinical outcomes. We used genetic variants across 94 kidney function loci identified in the trans-ethnic meta-analyses of the COGENT-Kidney Consortium to construct an “instrumental variable” for eGFR. Clinical outcomes were obtained from ICD codes in the UK Biobank. The graph shows the Mendelian Randomization effect size (and standard deviation) of eGFR on outcomes for aggregated variants under inverse variance weighted regression. Note that low eGFR is casually associated with CKD stage 5, glomerular disease and hypertensive renal disease, but has an inverse causal association with kidney stones.

Figure 2. Examples of improved fine-mapping resolution attained through trans-ethnic meta-analysis (312,468 individuals) over European ancestry meta-analysis (134,070 individuals) in the COGENT-Kidney Consortium.

Each point represents a variant, plotted with their p-value (on a -log₁₀ scale) as a function of genomic position (NCBI build 37). In each plot, the index variant is represented by the purple symbol. The colour coding of all other variants indicates LD with the index variant in European ancestry haplotypes from the 1000 Genomes Project reference panel: red r²≥0.8; gold 0.6≤r²<0.8; green 0.4≤r²<0.6; cyan 0.2≤r²<0.4; blue r²<0.2; grey r² unknown. Recombination rates are estimated from Phase II HapMap and gene annotations are taken from the University of California Santa Cruz genome browser.