Genome-Wide Association Study of CKD Progression
Authors: Robinson-Cohen Cassianne , Triozzi Jefferson L. , Rowan Bryce , He Jing , Chen Hua C. , Zheng Neil S. , Wei Wei-Qi , Wilson Otis D. , Hellwege Jacklyn N. , Tsao Philip S. , Gaziano J. Michael , Bick Alexander , Matheny Michael E. , Chung Cecilia P. , Lipworth Loren , Siew Edward D. , Ikizler T. Alp , Tao Ran , Hung Adriana M. 
Published: June 2023

Significance Statement
Rapid progression of CKD is associated with poor clinical outcomes. Most previous studies looking for genetic factors associated with low eGFR have used cross-sectional data. The authors conducted a meta-analysis of genome-wide association studies of eGFR decline among 116,870 participants with CKD, focusing on longitudinal data. They identified three loci (two of them novel) associated with longitudinal eGFR decline. In addition to the known UMOD/
PDILT locus, variants within BICC1 were associated with significant differences in longitudinal eGFR slope. Variants within HEATR4 also were associated with differences in eGFR decline, but only among Black/African American individuals without diabetes. These findings help characterize molecular mechanisms of eGFR decline in CKD and may inform new therapeutic approaches for progressive kidney disease.

Background
Rapid progression of CKD is associated with poor clinical outcomes. Despite extensive study of the genetics of cross-sectional eGFR, only a few loci associated with eGFR decline over time have been identified.

Methods
We performed a meta-analysis of genome-wide association studies of eGFR decline among 116,870 participants with CKD—defined by two outpatient eGFR measurements of <60 ml/min per 1.73 m2, obtained 90–365 days apart—from the Million Veteran Program and Vanderbilt University Medical Center's DNA biobank. The primary outcome was the annualized relative slope in outpatient eGFR. Analyses were stratified by ethnicity and diabetes status and meta-analyzed thereafter.

Results
In cross-ancestry meta-analysis, the strongest association was rs77924615, near UMOD/PDILT; each copy of the G allele was associated with a 0.30%/yr faster eGFR decline (P = 4.9×10−27). We also observed an association within BICC1 (rs11592748), where every additional minor allele was associated with a 0.13%/yr slower eGFR decline (P = 5.6×10−9). Among participants without diabetes, the strongest association was the UMOD/PDILT variant rs36060036, associated with a 0.27%/yr faster eGFR decline per copy of the C allele (P = 1.9×10−17). Among Black participants, a significantly faster eGFR decline was associated with variant rs16996674 near APOL1 (R2=0.29 with the G1 high-risk genotype); among Black participants with diabetes, lead variant rs11624911 near HEATR4 also was associated with a significantly faster eGFR decline. We also nominally replicated loci with known associations with eGFR decline, near PRKAG2, FGF5, and C15ORF54.

Conclusions
Three loci were significantly associated with longitudinal eGFR change at genome-wide significance. These findings help characterize molecular mechanisms of eGFR decline and may contribute to the development of new therapeutic approaches for progressive CKD.