Genome-wide meta-analysis identifies new candidate genes for sickle cell disease nephropathy.

Sickle cell disease nephropathy (SCDN), a common sickle cell disease (SCD) complication, is strongly associated with mortality. Polygenic risk scores calculated from recent trans-ethnic meta-analyses of urinary albumin-to-creatinine ratio (UACR) and estimated glomerular filtration rate (eGFR) trended toward association with proteinuria and eGFR in SCD but the model fit was poor (R2<0.01), suggesting that there are likely unique genetic risk factors for SCDN. Therefore, we performed genome-wide association studies (GWAS) for two critical manifestations of SCDN, proteinuria and decreased eGFR, in two well-characterized adult SCD cohorts, representing the largest SCDN sample to date. Meta-analysis identified six genome-wide significant associations (false discovery rate [FDR] q≤0.05): three for proteinuria (CRYL1, VWF, ADAMTS7) and three for eGFR (LRP1B, linc02288, and FPGT-TNNI3K/TNNI3K). These associations are independent of APOL1 risk and represent novel SCDN loci, many with evidence for regulatory function. Moreover, GWAS SNPs in CRYL1, VWF, ADAMTS7, and linc02288 are also associated with gene expression in kidney and pathways important to both renal function and SCD biology, supporting the hypothesis that SCDN pathophysiology is distinct from other forms of kidney disease. Together, these findings provide new targets for functional follow-up that could be tested prospectively and potentially used to identify SCD patients at risk prior to kidney dysfunction onset.