Genome-Wide Association and Trans-ethnic Meta-Analysis for Advanced Diabetic Kidney Disease: Family Investigation of Nephropathy and Diabetes (FIND)

Diabetic kidney disease (DKD) is the most common etiology of chronic kidney disease (CKD) in the industrialized world and accounts for much of the excess mortality in patients with diabetes mellitus. Approximately 45% of U.S. patients with incident end-stage kidney disease (ESKD) have DKD. Independent of glycemic control, DKD aggregates in families and has higher incidence rates in African, Mexican, and American Indian ancestral groups relative to European populations. The Family Investigation of Nephropathy and Diabetes (FIND) performed a genome-wide association study (GWAS) contrasting 6,197 unrelated individuals with advanced DKD with healthy and diabetic individuals lacking nephropathy of European American, African American, Mexican American, or American Indian ancestry. A large-scale replication and trans-ethnic meta-analysis included 7,539 additional European American, African American and American Indian DKD cases and non-nephropathy controls. Within ethnic group meta-analysis of discovery GWAS and replication set results identified genome-wide significant evidence for association between DKD and rs12523822 on chromosome 6q25.2 in American Indians (P = 5.74x10-9). The strongest signal of association in the trans-ethnic meta-analysis was with a SNP in strong linkage disequilibrium with rs12523822 (rs955333; P = 1.31x10-8), with directionally consistent results across ethnic groups. These 6q25.2 SNPs are located between the SCAF8 and CNKSR3 genes, a region with DKD relevant changes in gene expression and an eQTL with IPCEF1, a gene co-translated with CNKSR3. Several other SNPs demonstrated suggestive evidence of association with DKD, within and across populations. These data identify a novel DKD susceptibility locus with consistent directions of effect across diverse ancestral groups and provide insight into the genetic architecture of DKD

Genome-Wide Association and Trans-ethnic Meta-Analysis for Advanced Diabetic Kidney Disease: Family Investigation of Nephropathy and Diabetes (FIND).

Diabetic kidney disease (DKD) is the most common etiology of chronic kidney disease (CKD) in the industrialized world and accounts for much of the excess mortality in patients with diabetes mellitus. Approximately 45% of U.S. patients with incident end-stage kidney disease (ESKD) have DKD. Independent of glycemic control, DKD aggregates in families and has higher incidence rates in African, Mexican, and American Indian ancestral groups relative to European populations. The Family Investigation of Nephropathy and Diabetes (FIND) performed a genome-wide association study (GWAS) contrasting 6,197 unrelated individuals with advanced DKD with healthy and diabetic individuals lacking nephropathy of European American, African American, Mexican American, or American Indian ancestry. A large-scale replication and trans-ethnic meta-analysis included 7,539 additional European American, African American and American Indian DKD cases and non-nephropathy controls. Within ethnic group meta-analysis of discovery GWAS and replication set results identified genome-wide significant evidence for association between DKD and rs12523822 on chromosome 6q25.2 in American Indians (P = 5.74x10-9). The strongest signal of association in the trans-ethnic meta-analysis was with a SNP in strong linkage disequilibrium with rs12523822 (rs955333; P = 1.31x10-8), with directionally consistent results across ethnic groups. These 6q25.2 SNPs are located between the SCAF8 and CNKSR3 genes, a region with DKD relevant changes in gene expression and an eQTL with IPCEF1, a gene co-translated with CNKSR3. Several other SNPs demonstrated suggestive evidence of association with DKD, within and across populations. These data identify a novel DKD susceptibility locus with consistent directions of effect across diverse ancestral groups and provide insight into the genetic architecture of DKD

Demographic characteristics of study populations.

<p><b>† In the African American sample, we obtained out-of-study samples from Wake Forest University and Howard University (see</b><a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1005352#sec009" target="_blank">Methods</a><b>). Their demographic characteristics are as follows: 931 DKD cases are 60.3% female, Age in years 61.6 ± 10.5, DM duration in years 19.7 ± 10.7; 92 Diabetic controls are all female, Age in years 55.1 ± 11.6, No Diabetes duration available; 1288 Non-Diabetic controls are 35.5% female, Age in years 48.0 ± 12.4. FILR–FIND Large Replication study.</b></p><p>Demographic characteristics of study populations.</p

Manhattan plot of FIND GWAS meta-analysis associations across ancestries included in Discovery and Replication samples.

<p>Manhattan plot of FIND GWAS meta-analysis associations across ancestries included in Discovery and Replication samples.</p

Top GWAS associations, by ethnicity.

<p>¹ P-values shown are additive unless another model is denoted next to the p-value (d = dominant model, r = recessive model). RA is risk allele. The odds ratio (OR) is presented for the risk allele, compared with the non-risk allele, for a given model. Direction (discovery) is read in the order: AA-AI-EA-MA; Direction (replication) is read in the order: AA-AI-EA; a “?” denotes that ethnicity’s data did not pass QC and was not included in the meta-analysis. A “+” or “-”indicates the direction of the effect in individuals of a specific ancestry.</p><p>Top GWAS associations, by ethnicity.</p

Zoom plot of the <i>SCAF8</i> gene region (trans-ancestry meta-analysis across Discovery and Replication samples).

<p>Squares denote SNPs in the Replication Study, Circles are SNPs that are only present in the GWAS, so the P-values shown reflect the GWAS Trans-Ancestry Meta-Analysis. The Ad-Mixed American population in 1000 Genomes was used for LD information.</p

Trans-ethnic meta-analysis GWAS results, across Discovery and Replication samples.

<p>Direction: RA is risk allele. The odds ratio (OR) is presented for the risk allele, compared with the non-risk allele, for a given model. The FIND ancestry groups are presented in the following order: AA-AI-EA-MA. A “+” or “-”indicates the direction of the effect in individuals of a specific ancestry. A “?” denotes that the indicated SNP did not pass QC in that ancestry and the results were not included in the meta-analysis. *a, additive; r, recessive; d, dominant</p><p>Trans-ethnic meta-analysis GWAS results, across Discovery and Replication samples.</p