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Transferability and fine-mapping of glucose and insulin quantitative trait loci across populations: CARe, the Candidate Gene Association Resource
Ist Teil von
Diabetologia, 2012-11, Vol.55 (11), p.2970-2984
Ort / Verlag
Berlin/Heidelberg: Springer-Verlag
Erscheinungsjahr
2012
Quelle
MEDLINE
Beschreibungen/Notizen
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.