Abstract P346: Genome-wide Association Study of Chronic Kidney Disease
Authors: Changwei Li, Tanika N Kelly, Dingding Zhang, Luqi Shen, Jing Chen, Jiang He
Journal: Circulation (2017)

Objectives: The current study aimed to identify genetic variants influencing chronic kidney disease (CKD) by conducting genome-wide association study (GWAS) among participants from the Atherosclerosis Risk in Communities Study (ARIC) and the Chronic Renal Insufficiency Cohort (CRIC). Methods: We conducted a case-control GWAS of CKD, combining data from the ARIC and CRIC studies to generate our discovery stage sample. CKD was defined as an estimated glomerular filtration rate (eGFR) &lt;60 ml/min/1.73m 2 at baseline or during follow-up in each cohort. Logistic regression models were used to test genome-wide SNP effects on CKD, adjusting for age, gender, hypertension, diabetes, and the first 10 principal components, among 3,855 Blacks (1,541 CKD cases) and 10,096 Whites (2,194 CKD cases), separately. SNPs with discovery stage P &lt;1.00х10 -5 were evaluated for replication among participants of the Women’s Health Initiative (WHI). We also performed conditional analyses, including the lead SNP in a model with all other significant SNPs in the region, separately, to identify any additional independent variants at each locus. Results: We identified 7 and 5 novel loci for Blacks and Whites, respectively. Intergenic variants rs9396438 (ARIC&amp;CRIC P =3.38х10 -9 , WHI P =4.32х10 -2 , and meta P =9.09х10 -9 ), rs56687683 (ARIC&amp;CRIC P =8.64х10 -11 , WHI P =3.58х10 -2 , and meta P =7.97х10 -10 ), and rs6071452 (ARIC&amp;CRIC P =3.02х10 -11 , WHI P =4.50х10 -2 , and meta P =2.10х10 -10 ), SNX9 variant rs10945790 (ARIC&amp;CRIC P =3.67х10 -10 , WHI P =2.05х10 -2 , and meta P =2.00х10 -10 ), and NXN variant rs10153287 (ARIC&amp;CRIC P =2.32х10 -7 , WHI P =1.61х10 -2 , and meta P =1.75х10 -8 ) were robustly associated with CKD among Blacks. Intergenic variants rs509616 (ARIC&amp;CRIC P =2.86х10 -19 , WHI P =3.44х10 -2 , and meta P =5.97х10 -19 ), rs35849486 (ARIC&amp;CRIC P =6.66х10 -7 , WHI P =1.79х10 -2 , and meta P =3.95х10 -8 ), rs12508057 (ARIC&amp;CRIC P =2.57х10 -9 , WHI P =2.45х10 -2 , and meta P =2.48х10 -10 ), and rs2180911 (ARIC&amp;CRIC P =3.75х10 -7 , WHI P =1.53х10 -2 , and meta P =2.11х10 -8 ), MEGF6 variant rs34852522 (ARIC&amp;CRIC P =6.01х10 -7 , WHI P =2.30х10 -2 , and meta P =4.20х10 -8 ), CAPN8 variant rs34485635 (ARIC&amp;CRIC P =9.58х10 -10 , WHI P =2.27х10 -2 , and meta P =1.01х10 -10 ), and PTPRS variant rs80125132 (ARIC&amp;CRIC P =4.38х10 -7 , WHI P =1.74х10 -2 , and meta P =3.05х10 -8 ) were identified for Whites. Furthermore, conditional analyses at the above loci additionally identified CAPN8 missense variant rs4072247 ( P =6.30х10 -8 ) at the rs34485635 locus and NKX3-2 UTR 3-primer variant rs3822226 ( P =4.08х10 -14 ) at the rs12508057 locus for CKD among Whites. Finally, we replicated 9 and 39 loci reported in previous CKD GWAS among Whites and Blacks, respectively. Conclusion: We robustly identified 12 novel loci in our large-scale case-control GWAS of CKD. In addition, conditional analyses identified additional functional signals at 2 novel loci among Whites.