Dataset Information

Transferability and fine-mapping of glucose and insulin quantitative trait loci across populations: CARe, the Candidate Gene Association Resource.

ABSTRACT: Hyperglycaemia disproportionately affects African-Americans (AfAs). We tested the transferability of 18 single-nucleotide polymorphisms (SNPs) associated with glycaemic traits identified in European ancestry (EuA) populations in 5,984 non-diabetic AfAs.We meta-analysed SNP associations with fasting glucose (FG) or insulin (FI) in AfAs from five cohorts in the Candidate Gene Association Resource. We: (1) calculated allele frequency differences, variations in linkage disequilibrium (LD), fixation indices (F(st)s) and integrated haplotype scores (iHSs); (2) tested EuA SNPs in AfAs; and (3) interrogated within ± 250 kb around each EuA SNP in AfAs.Allele frequency differences ranged from 0.6% to 54%. F(st) exceeded 0.15 at 6/16 loci, indicating modest population differentiation. All iHSs were <2, suggesting no recent positive selection. For 18 SNPs, all directions of effect were the same and 95% CIs of association overlapped when comparing EuA with AfA. For 17 of 18 loci, at least one SNP was nominally associated with FG in AfAs. Four loci were significantly associated with FG (GCK, p = 5.8 × 10(-8); MTNR1B, p = 8.5 × 10(-9); and FADS1, p = 2.2 × 10(-4)) or FI (GCKR, p = 5.9 × 10(-4)). At GCK and MTNR1B the EuA and AfA SNPs represented the same signal, while at FADS1, and GCKR, the EuA and best AfA SNPs were weakly correlated (r(2) <0.2), suggesting allelic heterogeneity for association with FG at these loci.Few glycaemic SNPs showed strict evidence of transferability from EuA to AfAs. Four loci were significantly associated in both AfAs and those with EuA after accounting for varying LD across ancestral groups, with new signals emerging to aid fine-mapping.

SUBMITTER: Liu CT

PROVIDER: S-EPMC3804308 | biostudies-literature | 2012 Nov

REPOSITORIES: biostudies-literature

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Transferability and fine-mapping of glucose and insulin quantitative trait loci across populations: CARe, the Candidate Gene Association Resource.

Liu C-T CT Ng M C Y MC Rybin D D Adeyemo A A Bielinski S J SJ Boerwinkle E E Borecki I I Cade B B Chen Y D I YD Djousse L L Fornage M M Goodarzi M O MO Grant S F A SF Guo X X Harris T T Kabagambe E E Kizer J R JR Liu Y Y Lunetta K L KL Mukamal K K Nettleton J A JA Pankow J S JS Patel S R SR Ramos E E Rasmussen-Torvik L L Rich S S SS Rotimi C N CN Sarpong D D Shriner D D Sims M M Zmuda J M JM Redline S S Kao W H WH Siscovick D D Florez J C JC Rotter J I JI Dupuis J J Wilson J G JG Bowden D W DW Meigs J B JB

Diabetologia 20120816 11

<h4>Aims/hypothesis</h4>Hyperglycaemia disproportionately affects African-Americans (AfAs). We tested the transferability of 18 single-nucleotide polymorphisms (SNPs) associated with glycaemic traits identified in European ancestry (EuA) populations in 5,984 non-diabetic AfAs.<h4>Methods</h4>We meta-analysed SNP associations with fasting glucose (FG) or insulin (FI) in AfAs from five cohorts in the Candidate Gene Association Resource. We: (1) calculated allele frequency differences, variations i ...[more]

PMID: 22893027

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Project description:BackgroundSingle nucleotide polymorphisms (SNPs) which capture a significant impact on a trait can be identified with genome-wide association studies. High linkage disequilibrium (LD) among SNPs makes it difficult to identify causative variants correctly. Thus, often target regions instead of single SNPs are reported. Sample size has not only a crucial impact on the precision of parameter estimates, it also ensures that a desired level of statistical power can be reached. We study the design of experiments for fine-mapping of signals of a quantitative trait locus in such a target region.MethodsA multi-locus model allows to identify causative variants simultaneously, to state their positions more precisely and to account for existing dependencies. Based on the commonly applied SNP-BLUP approach, we determine the z-score statistic for locally testing non-zero SNP effects and investigate its distribution under the alternative hypothesis. This quantity employs the theoretical instead of observed dependence between SNPs; it can be set up as a function of paternal and maternal LD for any given population structure.ResultsWe simulated multiple paternal half-sib families and considered a target region of 1 Mbp. A bimodal distribution of estimated sample size was observed, particularly if more than two causative variants were assumed. The median of estimates constituted the final proposal of optimal sample size; it was consistently less than sample size estimated from single-SNP investigation which was used as a baseline approach. The second mode pointed to inflated sample sizes and could be explained by blocks of varying linkage phases leading to negative correlations between SNPs. Optimal sample size increased almost linearly with number of signals to be identified but depended much stronger on the assumption on heritability. For instance, three times as many samples were required if heritability was 0.1 compared to 0.3. An R package is provided that comprises all required tools.ConclusionsOur approach incorporates information about the population structure into the design of experiments. Compared to a conventional method, this leads to a reduced estimate of sample size enabling the resource-saving design of future experiments for fine-mapping of candidate variants.

Dataset Information

Transferability and fine-mapping of glucose and insulin quantitative trait loci across populations: CARe, the Candidate Gene Association Resource.

Publications

Transferability and fine-mapping of glucose and insulin quantitative trait loci across populations: CARe, the Candidate Gene Association Resource.

Similar Datasets

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