Transferability and fine-mapping of glucose and insulin quantitative trait loci across populations: CARe, the Candidate Gene Association Resource.
OBJECTIVE
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
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.
Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA.
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Liu
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Rybin
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Adeyemo
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Bielinski
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Boerwinkle
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Borecki
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Cade
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Chen
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Djousse
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Fornage
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Goodarzi
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Grant
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Guo
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Harris
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Kabagambe
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Kizer
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Liu
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Lunetta
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Mukamal
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Nettleton
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Pankow
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Patel
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Ramos
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Shriner
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Meigs
D000328:Adult; D001741:Black or African American / Q000235:genetics / Q000706:statistics & numerical data; D000368:Aged; D000369:Aged, 80 and over; D001786:Blood Glucose / Q000235:genetics*; D030541:Databases, Genetic / Q000706:statistics & numerical data; D000090943:Delta-5 Fatty Acid Desaturase; D003924:Diabetes Mellitus, Type 2 / Q000208:ethnology* / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease / Q000208:ethnology / Q000235:genetics; D006801:Humans; D006943:Hyperglycemia / Q000208:ethnology* / Q000235:genetics*; D007328:Insulin / Q000235:genetics*; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D040641:Quantitative Trait Loci / Q000235:genetics; D012307:Risk Factors; D044465:White People / Q000235:genetics / Q000706:statistics & numerical data; D055815:Young Adult
D001786:Blood Glucose; D000090943:Delta-5 Fatty Acid Desaturase; D007328:Insulin; C000716847:FADS1 protein, human