Genomewide linkage scan for diabetic renal failure and albuminuria: the FIND study

Abstract

Background: Diabetic nephropathy (DN) is a leading cause of mortality and morbidity in patients with type 1 and type 2 diabetes. The multicenter FIND consortium aims to identify genes for DN and its associated quantitative traits, e.g. the urine albumin:creatinine ratio (ACR). Herein, the results of whole-genome linkage analysis and a sparse association scan for ACR and a dichotomous DN phenotype are reported in diabetic individuals.

Methods: A genomewide scan comprising more than 5,500 autosomal single nucleotide polymorphism markers (average spacing of 0.6 cM) was performed on 1,235 nuclear and extended pedigrees (3,972 diabetic participants) ascertained for DN from African-American (AA), American-Indian (AI), European-American (EA) and Mexican-American (MA) populations.

Results: Strong evidence for linkage to DN was detected on chromosome 6p (p = 8.0 × 10(-5), LOD = 3.09) in EA families as well as suggestive evidence for linkage to chromosome 7p in AI families. Regions on chromosomes 3p in AA, 7q in EA, 16q in AA and 22q in MA displayed suggestive evidence of linkage for urine ACR. The linkage peak on chromosome 22q overlaps the MYH9/APOL1 gene region, previously implicated in AA diabetic and nondiabetic nephropathies.

Conclusion: These results strengthen the evidence for previously identified genomic regions and implicate several novel loci potentially involved in the pathogenesis of DN.

Copyright © 2011 S. Karger AG, Basel.

Figures

Fig. 1

Autosomal genomewide model-free linkage scan for DN. From top to bottom, panels display results for AA, AI, EA and MA samples, as well as pooled Fisher p values from all study samples (All).

Fig. 2

Detailed linkage and association results for DN for segments of chromosomes 6 (a), 7 (b), 18 (c, e) and 22 (d, f, g). Heavy lines trace linkage results for AA, AI, EA and MA samples, as well as combined Fisher p values (alternating dots and dashes). Tick marks at the top show the location of Illumina IV SNPs. In panel e, results from association analysis for AI (·) are shown along with the linkage profile from panel c. In panels f and g, association results for AI and EA are shown (·), respectively, with the linkage profiles from panel d.

Fig. 3

Genomewide linkage scan for ACR, adjusted for sex and age at DM diagnosis. See legend of fig. 1 for explanation of plots and symbols.

Fig. 4

Detailed linkage and association results for ACR, on segments of chromosomes 3 (a), 7 (b), 21 (c, e) and 22 (d). Axes and lines are as in figure 2. In panel e, results from association analysis for the AA sample are shown (·) with the AA linkage profile from panel c.