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

Sickle cell disease nephropathy (SCDN), a common SCD complication, is strongly associated with mortality. Polygenic risk scores calculated from recent transethnic meta-analyses of urinary albumin-to-creatinine ratio and estimated glomerular filtration rate (eGFR) trended toward association with proteinuria and eGFR in SCD but the model fit was poor (R(2) < 0.01), suggesting that there are likely unique genetic risk factors for SCDN. Therefore, we performed genome-wide association studies (GWAS) for 2 critical manifestations of SCDN, proteinuria and decreased eGFR, in 2 well-characterized adult SCD cohorts, representing, to the best of our knowledge, the largest SCDN sample to date. Meta-analysis identified 6 genome-wide significant associations (false discovery rate, q ≤ 0.05): 3 for proteinuria (CRYL1, VWF, and ADAMTS7) and 3 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 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 patients with SCD who are at risk, before onset of kidney dysfunction.