A genome-wide search for linkage of estimated glomerular filtration rate (eGFR) in the Family Investigation of Nephropathy and Diabetes (FIND).

Estimated glomerular filtration rate (eGFR), a measure of kidney function, is heritable, suggesting that genes influence renal function. Genes that influence eGFR have been identified through genome-wide association studies. However, family-based linkage approaches may identify loci that explain a larger proportion of the heritability. This study used genome-wide linkage and association scans to identify quantitative trait loci (QTL) that influence eGFR.Genome-wide linkage and sparse association scans of eGFR were performed in families ascertained by probands with advanced diabetic nephropathy (DN) from the multi-ethnic Family Investigation of Nephropathy and Diabetes (FIND) study. This study included 954 African Americans (AA), 781 American Indians (AI), 614 European Americans (EA) and 1,611 Mexican Americans (MA). A total of 3,960 FIND participants were genotyped for 6,000 single nucleotide polymorphisms (SNPs) using the Illumina Linkage IVb panel. GFR was estimated by the Modification of Diet in Renal Disease (MDRD) formula.The non-parametric linkage analysis, accounting for the effects of diabetes duration and BMI, identified the strongest evidence for linkage of eGFR on chromosome 20q11 (log of the odds [LOD] = 3.34; P = 4.4 × 10(-5)) in MA and chromosome 15q12 (LOD = 2.84; P = 1.5 × 10(-4)) in EA. In all subjects, the strongest linkage signal for eGFR was detected on chromosome 10p12 (P = 5.5 × 10(-4)) at 44 cM near marker rs1339048. A subsequent association scan in both ancestry-specific groups and the entire population identified several SNPs significantly associated with eGFR across the genome.The present study describes the localization of QTL influencing eGFR on 20q11 in MA, 15q21 in EA and 10p12 in the combined ethnic groups participating in the FIND study. Identification of causal genes/variants influencing eGFR, within these linkage and association loci, will open new avenues for functional analyses and development of novel diagnostic markers for DN

A Genome-Wide Search for Linkage of Estimated Glomerular Filtration Rate (eGFR) in the Family Investigation of Nephropathy and Diabetes (FIND)

Estimated glomerular filtration rate (eGFR), a measure of kidney function, is heritable, suggesting that genes influence renal function. Genes that influence eGFR have been identified through genome-wide association studies. However, family-based linkage approaches may identify loci that explain a larger proportion of the heritability. This study used genome-wide linkage and association scans to identify quantitative trait loci (QTL) that influence eGFR.Genome-wide linkage and sparse association scans of eGFR were performed in families ascertained by probands with advanced diabetic nephropathy (DN) from the multi-ethnic Family Investigation of Nephropathy and Diabetes (FIND) study. This study included 954 African Americans (AA), 781 American Indians (AI), 614 European Americans (EA) and 1,611 Mexican Americans (MA). A total of 3,960 FIND participants were genotyped for 6,000 single nucleotide polymorphisms (SNPs) using the Illumina Linkage IVb panel. GFR was estimated by the Modification of Diet in Renal Disease (MDRD) formula.The non-parametric linkage analysis, accounting for the effects of diabetes duration and BMI, identified the strongest evidence for linkage of eGFR on chromosome 20q11 (log of the odds [LOD] = 3.34; P = 4.4 × 10(-5)) in MA and chromosome 15q12 (LOD = 2.84; P = 1.5 × 10(-4)) in EA. In all subjects, the strongest linkage signal for eGFR was detected on chromosome 10p12 (P = 5.5 × 10(-4)) at 44 cM near marker rs1339048. A subsequent association scan in both ancestry-specific groups and the entire population identified several SNPs significantly associated with eGFR across the genome.The present study describes the localization of QTL influencing eGFR on 20q11 in MA, 15q21 in EA and 10p12 in the combined ethnic groups participating in the FIND study. Identification of causal genes/variants influencing eGFR, within these linkage and association loci, will open new avenues for functional analyses and development of novel diagnostic markers for DN

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

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

Genomewide Linkage Scan for Diabetic Renal Failure and Albuminuria: The FIND Study

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

Clinical characteristics of the genotyped individuals.

<p>ACR-Albumin:Creatinine Ratio; PCR-Protein:Creatinine Ratio; eGFR-estimated Glomerular Filtration Rate using modified MDRD equation Values are expressed as either N (%) or median (1st quartile, 3rd quartile).</p

Figure 2

<p>Figure 2a. The figure shows the linkage of eGFR on 10p12 after accounting for the covariate effects of BMI and diabetes duration in the population-specific and combined analysis. A black dot denotes the location of rs1345561 (62.24 cM) that is associated with eGFR in African American participants (P  =  3.1 × 10⁻⁴) after accounting for the covariate effects of BMI and diabetes duration. AA-African Americans; AI-American Indians; EA-European Americans; MA-Mexican Americans, cM-Centi Morgans. Figure 2b.The figure shows the linkage of eGFR on 20q11 after accounting for the covariate effects of BMI and diabetes duration in the population-specific and combined analysis. The green and black dots denote the location of rs1885567 (43.47 cM) rs968478 (75.75 cM) that are associated with eGFR in MA (P  =  0034) and AA (P = 0.0018) respectively. AA-African Americans; AI-American Indians; EA-European Americans; MA-Mexican Americans; cM-Centi Morgans.</p

This figure shows the results of the genome-wide linkage scan for eGFR in population-specific and population-combined analysis that accounted the covariate effects of BMI and diabetes duration.

<p>AA-African Americans; AI-American Indians; EA-European Americans; MA-Mexican Americans, cM-Centi Morgans.</p

Major linkage peaks identified for the eGFR in population-specific and in population-combined analysis.

<p>Group, ethnic group (AA = African American, AI = American Indian, EA = European American, MA = Mexican American); cM, centimorgans on the deCODE linkage map; Baseline, eGFR without covariate adjustment; Covariates, eGFR adjusted for BMI and diabetes duration. Reported <i>p</i> values are asymptotic.</p

Most significantly associated SNPs with eGFR in population-specific and in population-combined analysis.

<p>SNPs with at least one <i>p</i> value less than 0.001 in an ethnic-specific or in the overall analysis are shown. Chrom, Chromosome; SNP, Single Nucleotide Polymorphism; cM, centimorgans; AA, African American; AI, American Indian; EA, European American; MA, Mexican American; NA, Not applicable;</p><p>*, Adjusted for the covariate effects of BMI and diabetes duration.</p