Transferability and fine-Mapping of glucose and insulin quantitative trait loci across populations: CARe, the candidate gene association resource

C. T. Liu, M. C Y Ng, D. Rybin, A. Adeyemo, Suzette J Bielinski, E. Boerwinkle, I. Borecki, B. Cade, Y. D I Chen, L. Djousse, M. Fornage, M. O. Goodarzi, S. F A Grant, X. Guo, T. Harris, E. Kabagambe, J. R. Kizer, Y. Liu, K. L. Lunetta, K. MukamalJ. A. Nettleton, J. S. Pankow, S. R. Patel, E. Ramos, L. Rasmussen-Torvik, S. S. Rich, C. N. Rotimi, D. Sarpong, D. Shriner, M. Sims, J. M. Zmuda, S. Redline, W. H. Kao, D. Siscovick, J. C. Florez, J. I. Rotter, J. Dupuis, J. G. Wilson, D. W. Bowden, J. B. Meigs

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

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 (Fsts) 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%. Fst 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.

Original languageEnglish (US)
Pages (from-to)2970-2984
Number of pages15
JournalDiabetologia
Volume55
Issue number11
DOIs
StatePublished - Nov 2012

Fingerprint

Quantitative Trait Loci
Single Nucleotide Polymorphism
African Americans
Insulin
Glucose
Population
Genes
Fasting
Linkage Disequilibrium
Gene Frequency
Haplotypes
Hyperglycemia

Keywords

  • African ancestry
  • Genetics
  • Genome-wide association
  • LD mapping
  • Minorities
  • Type 2 diabetes

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Transferability and fine-Mapping of glucose and insulin quantitative trait loci across populations : CARe, the candidate gene association resource. / Liu, C. T.; Ng, M. C Y; Rybin, D.; Adeyemo, A.; Bielinski, Suzette J; Boerwinkle, E.; Borecki, I.; Cade, B.; Chen, Y. D I; Djousse, L.; Fornage, M.; Goodarzi, M. O.; Grant, S. F A; Guo, X.; Harris, T.; Kabagambe, E.; Kizer, J. R.; Liu, Y.; Lunetta, K. L.; Mukamal, K.; Nettleton, J. A.; Pankow, J. S.; Patel, S. R.; Ramos, E.; Rasmussen-Torvik, L.; Rich, S. S.; Rotimi, C. N.; Sarpong, D.; Shriner, D.; Sims, M.; Zmuda, J. M.; Redline, S.; Kao, W. H.; Siscovick, D.; Florez, J. C.; Rotter, J. I.; Dupuis, J.; Wilson, J. G.; Bowden, D. W.; Meigs, J. B.

In: Diabetologia, Vol. 55, No. 11, 11.2012, p. 2970-2984.

Research output: Contribution to journalArticle

Liu, CT, Ng, MCY, Rybin, D, Adeyemo, A, Bielinski, SJ, Boerwinkle, E, Borecki, I, Cade, B, Chen, YDI, Djousse, L, Fornage, M, Goodarzi, MO, Grant, SFA, 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 2012, 'Transferability and fine-Mapping of glucose and insulin quantitative trait loci across populations: CARe, the candidate gene association resource', Diabetologia, vol. 55, no. 11, pp. 2970-2984. https://doi.org/10.1007/s00125-012-2656-4
Liu, C. T. ; Ng, M. C Y ; Rybin, D. ; Adeyemo, A. ; Bielinski, Suzette J ; Boerwinkle, E. ; Borecki, I. ; Cade, B. ; Chen, Y. D I ; Djousse, L. ; Fornage, M. ; Goodarzi, M. O. ; Grant, S. F A ; Guo, X. ; Harris, T. ; Kabagambe, E. ; Kizer, J. R. ; Liu, Y. ; Lunetta, K. L. ; Mukamal, K. ; Nettleton, J. A. ; Pankow, J. S. ; Patel, S. R. ; Ramos, E. ; Rasmussen-Torvik, L. ; Rich, S. S. ; Rotimi, C. N. ; Sarpong, D. ; Shriner, D. ; Sims, M. ; Zmuda, J. M. ; Redline, S. ; Kao, W. H. ; Siscovick, D. ; Florez, J. C. ; Rotter, J. I. ; Dupuis, J. ; Wilson, J. G. ; Bowden, D. W. ; Meigs, J. B. / Transferability and fine-Mapping of glucose and insulin quantitative trait loci across populations : CARe, the candidate gene association resource. In: Diabetologia. 2012 ; Vol. 55, No. 11. pp. 2970-2984.
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abstract = "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 (Fsts) 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{\%}. Fst 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.",
keywords = "African ancestry, Genetics, Genome-wide association, LD mapping, Minorities, Type 2 diabetes",
author = "Liu, {C. T.} and Ng, {M. C Y} and D. Rybin and A. Adeyemo and Bielinski, {Suzette J} and E. Boerwinkle and I. Borecki and B. Cade and Chen, {Y. D I} and L. Djousse and M. Fornage and Goodarzi, {M. O.} and Grant, {S. F A} and X. Guo and T. Harris and E. Kabagambe and Kizer, {J. R.} and Y. Liu and Lunetta, {K. L.} and K. Mukamal and Nettleton, {J. A.} and Pankow, {J. S.} and Patel, {S. R.} and E. Ramos and L. Rasmussen-Torvik and Rich, {S. S.} and Rotimi, {C. N.} and D. Sarpong and D. Shriner and M. Sims and Zmuda, {J. M.} and S. Redline and Kao, {W. H.} and D. Siscovick and Florez, {J. C.} and Rotter, {J. I.} and J. Dupuis and Wilson, {J. G.} and Bowden, {D. W.} and Meigs, {J. B.}",
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TY - JOUR

T1 - Transferability and fine-Mapping of glucose and insulin quantitative trait loci across populations

T2 - CARe, the candidate gene association resource

AU - Liu, C. T.

AU - Ng, M. C Y

AU - Rybin, D.

AU - Adeyemo, A.

AU - Bielinski, Suzette J

AU - Boerwinkle, E.

AU - Borecki, I.

AU - Cade, B.

AU - Chen, Y. D I

AU - Djousse, L.

AU - Fornage, M.

AU - Goodarzi, M. O.

AU - Grant, S. F A

AU - Guo, X.

AU - Harris, T.

AU - Kabagambe, E.

AU - Kizer, J. R.

AU - Liu, Y.

AU - Lunetta, K. L.

AU - Mukamal, K.

AU - Nettleton, J. A.

AU - Pankow, J. S.

AU - Patel, S. R.

AU - Ramos, E.

AU - Rasmussen-Torvik, L.

AU - Rich, S. S.

AU - Rotimi, C. N.

AU - Sarpong, D.

AU - Shriner, D.

AU - Sims, M.

AU - Zmuda, J. M.

AU - Redline, S.

AU - Kao, W. H.

AU - Siscovick, D.

AU - Florez, J. C.

AU - Rotter, J. I.

AU - Dupuis, J.

AU - Wilson, J. G.

AU - Bowden, D. W.

AU - Meigs, J. B.

PY - 2012/11

Y1 - 2012/11

N2 - 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 (Fsts) 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%. Fst 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.

AB - 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 (Fsts) 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%. Fst 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.

KW - African ancestry

KW - Genetics

KW - Genome-wide association

KW - LD mapping

KW - Minorities

KW - Type 2 diabetes

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