Top 2% of Genome-Wide Polygenic Score Indicates 3 Times the Risk of CKD

A study published in Nature Medicine found that genetic testing through a genome-wide polygenic score (GPS) could detect people with an increased risk of chronic kidney disease (CKD) and also determined that the APOL1 genotype was an increased risk factor for CKD in people of African descent.

There were 19 candidate scores generated using 1000 Genomes linkage disequilibrium reference and summary statistics from genome-wide association studies (GWAS) for eGFR. The study used the UK Biobank, eMERGE, University of Alabama, and BioMe databases to collect data for this study. There were 6573 patients of European ancestry and 170,635 controls for the GPS population. There were 967 patients of African ancestry and 6191 controls to determine the effects derivation of APOL1.

There were significant differences in the mean polygenic risk across all populations, with a shift toward a higher risk in those with African ancestry compared with other populations. The shift was more pronounced when including APOL1 risk genotype. The polygenic risk score for CKD was higher in individuals with African ancestry compared with other populations independent of APOL1 as suggested by these data.

The study also found that the mean difference in risk allele frequencies between African and European populations was greater than an expected mean of 0, which indicated a higher frequency of risk alleles in African genomes. GPS had a highly reproducible performance (odds ratio [OR], 1.46; 95% CI, 1.43-1.48).

The GPS was also tested in 6 African ancestry cohorts, where the GPS had a pooled OR of 1.32 (95% CI, 1.26-1.38) in the combined meta-analysis. The risk of CKD for individuals in the top 2% of GPS score was 80% higher in the model without APOL1 and 170% higher in the model with APOL1 compared with the remaining 98% of individuals.

The GPS was used for 2 Latinx cohorts, which found a pooled OR of 1.42 (95% CI, 1.29-1.57) in the combined meta-analysis. The inclusion of APOL1 genotypes improved risk prediction in the Latinx cohorts. In 4 Asian cohorts the GPS had a pooled OR of 1.68 (95% CI, 1.45-2.06) although APOL1 genotypes were absent from these cohorts.

The top 2% of the risk score distribution was associated with 166% to 393% higher risk of CKD than for the remaining individuals in European (OR, 3.60; 95% CI, 3.11-4.17), African (OR, 2.66; 95% CI, 2.01-3.51), Latinx (OR, 4.93; 95% CI, 2.46-9.89), and Asian (OR, 3.81; 95% CI, 1.91-7.59) populations.

There were some limitations to this study. There was a lack of large-scale GWAs for kidney function in non-European populations and the existing cohorts were small in size. Performance comparisons between ancestral groups may have been biased by the differences in genotyping platforms used by various biobanks. Ancestry definitions varied in the cohorts used in this study, with 2 using genetic approaches and the others using self-report. This kept the study from assessing risks within the African American populations by country of origin.

The study score models polygenic effects from the GWAS rather than CKD. There were also differences in the mean and variance of the GPS distributions of ancestry. Lastly, the 2009 CKD-EPI was used in this study because of a lack of alternative at the time of the analyses.

The researchers concluded that their new GPS for CKD demonstrated that the polygenic component and APOL1 risk genotypes had effects on the risk of CKD. Individuals with the highest risk score distribution had an increased risk of getting CKD at about the equivalent of a positive family history.

Reference

Khan A, Turchin MC, Patki A, et al. Genome-wide polygenic score to predict chronic kidney disease across ancestries. Nat Med. Published online June 16, 2022. doi:10.1038/s41591-022-01869-1