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

Liu CT, Ng MC, Rybin D, Adeyemo A, Bielinski SJ, Boerwinkle E, Borecki I, Cade B, Chen YD, Djousse L, Fornage M, Goodarzi MO, Grant SF, Guo X, Harris T, Kabagambe E, Kizer JR, Liu Y, Lunetta KL, Mukamal K, Nettleton JA, Pankow JS, Patel SR, Ramos E, Rasmussen-Torvik L, Rich SS, Rotimi CN, Sarpong D, Shriner D, Sims M, Zmuda JM, Redline S, Kao WH, Siscovick D, Florez JC, Rotter JI, Dupuis J, Wilson JG, Bowden DW, Meigs JB
Diabetologia. 2012 55 (11): 2970-84

PMID: 22893027 · PMCID: PMC3804308 · DOI:10.1007/s00125-012-2656-4

AIMS/HYPOTHESIS - 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.

METHODS - 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.

RESULTS - 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.

CONCLUSIONS/INTERPRETATION - 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.

MeSH Terms (21)

Adult African Americans Aged Aged, 80 and over Blood Glucose Databases, Genetic Diabetes Mellitus, Type 2 European Continental Ancestry Group Female Gene Frequency Genetic Predisposition to Disease Humans Hyperglycemia Insulin Linkage Disequilibrium Male Middle Aged Polymorphism, Single Nucleotide Quantitative Trait Loci Risk Factors Young Adult

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