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Linkage disequilibrium analysis reveals an albuminuria risk haplotype containing three missense mutations in the cubilin gene with striking differences among European and African ancestry populations.

ABSTRACT: BACKGROUND: A recent meta-analysis described a variant (p.Ile2984Val) in the cubilin gene (CUBN) that is associated with levels of albuminuria in the general population and in diabetics. METHODS: We implemented a Linkage Disequilibrium (LD) search with data from the 1000 Genomes Project, on African and European population genomic sequences. RESULTS: We found that the p.Ile2984Val variation is part of a larger haplotype in European populations and it is almost absent in west Africans. This haplotype contains 19 single nucleotide polymorphisms (SNPs) in very high LD, three of which are missense mutations (p.Leu2153Phe, p.Ile2984Val, p.Glu3002Gly), and two have not been previously reported. Notably, this European haplotype is absent in west African populations, and the frequency of each individual polymorphism differs significantly in Africans. CONCLUSIONS: Genotyping of these variants in existing African origin sample sets coupled to measurements of urine albumin excretion levels should reveal which is the most likely functional candidate for albuminuria risk. The unique haplotypic structure of CUBN in different populations may leverage the effort to identify the functional variant and to shed light on evolution of the CUBN gene locus.

SUBMITTER: Tzur S

PROVIDER: S-EPMC3519576 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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Linkage disequilibrium analysis reveals an albuminuria risk haplotype containing three missense mutations in the cubilin gene with striking differences among European and African ancestry populations.

Tzur Shay S Wasser Walter G WG Rosset Saharon S Skorecki Karl K

BMC nephrology 20121031

<h4>Background</h4>A recent meta-analysis described a variant (p.Ile2984Val) in the cubilin gene (CUBN) that is associated with levels of albuminuria in the general population and in diabetics.<h4>Methods</h4>We implemented a Linkage Disequilibrium (LD) search with data from the 1000 Genomes Project, on African and European population genomic sequences.<h4>Results</h4>We found that the p.Ile2984Val variation is part of a larger haplotype in European populations and it is almost absent in west Af ...[more]

PMID: 23114252

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Project description:Linkage disequilibrium (LD) analysis provides information on the evolutionary aspects of populations. Recently, haplotype blocks have been used to increase the power of quantitative trait loci detection in genome-wide association studies and the prediction accuracy of genomic selection. Our objectives were as follows: to compare the degree of LD, LD decay, and LD decay extent in popcorn populations; to characterize the number and length of haplotype blocks in the populations; and to determine whether maize chromosomes also have a pattern of interspaced regions of high and low rates of recombination. We used a biparental population, a synthetic, and a breeding population, genotyped for approximately 75,000 single nucleotide polymorphisms (SNPs). The sample size ranged from 190 to 192 plants. For the whole-genome LD and haplotype block analyses, we assumed a window of 500 kb. To characterize the block and step patterns of LD in the populations, we constructed LD maps by chromosome, defining a cold spot as a chromosome segment including SNPs with the same LDU position. The LD and haplotype block analyses were also performed at the intragenic level, selecting 12 genes related to zein, starch, cellulose, and fatty acid biosynthesis. The populations with the higher and lower frequencies of |D'| values greater than 0.75 were the biparental (65-74%) and the breeding population (26-58%), respectively. There were slight differences between the populations regarding the average distance for SNPs with |D'| values greater than 0.75 (in the range of approximately 207 to 229 kb). The level of LD expressed by the r2 values was low in the populations (0.02, 0.04, and 0.04, on average) but comparable to some non-isolated human populations. The frequency of r2 values greater than 0.75 was lower in the biparental population (0.2-0.5%) and higher in the other populations (0.2-1.6%). The average distance for SNPs with r2 values greater than 0.75 was much higher in the biparental population (approximately 80 to 126 kb). In the other populations, the ranges were approximately 6 to 19 and 6 to 35 kb. The heatmaps for the regions covered by the first 100 SNPs in each chromosome, in each population (1 to 3.3 Mb, approximately), provided evidence that the comparatively few high r2 values (close to 1.0) occurred only for SNPs in close proximity, especially in the synthetic and breeding populations. Due to the reduced number of SNPs in the haplotype blocks (2 to 3) in the populations, it is not expected advantage of a haplotype-based association study as well as genomic selection along generations. The results concerning LD decay (rapid decay after 5-10 kb) and LD decay extent (along up to 300 kb) are in the range observed with maize inbred line panels. The LD maps indicate that maize chromosomes had a pattern of regions of extensive LD interspaced with regions of low LD. However, our simulated LD map provides evidence that this pattern can reflect regions with differences in allele frequencies and LD levels (expressed by |D'|) and not regions with high and low rates of recombination.

Dataset Information

Linkage disequilibrium analysis reveals an albuminuria risk haplotype containing three missense mutations in the cubilin gene with striking differences among European and African ancestry populations.

Publications

Linkage disequilibrium analysis reveals an albuminuria risk haplotype containing three missense mutations in the cubilin gene with striking differences among European and African ancestry populations.

Similar Datasets

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