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; S. 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. Mukamal; J. 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

doi:10.1007/s00125-012-2656-4

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, S. 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

Quantitative Health Sciences

Research output: Contribution to journal › Article › peer-review

19 Scopus citations

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 (F_sts) 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.

Original language	English (US)
Pages (from-to)	2970-2984
Number of pages	15
Journal	Diabetologia
Volume	55
Issue number	11
DOIs	https://doi.org/10.1007/s00125-012-2656-4
State	Published - Nov 2012

Keywords

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

ASJC Scopus subject areas

Internal Medicine
Endocrinology, Diabetes and Metabolism

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10.1007/s00125-012-2656-4

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Liu, C. T., Ng, M. C. Y., Rybin, D., Adeyemo, A., Bielinski, S. 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., ... Meigs, J. B. (2012). Transferability and fine-Mapping of glucose and insulin quantitative trait loci across populations: CARe, the candidate gene association resource. Diabetologia, 55(11), 2970-2984. https://doi.org/10.1007/s00125-012-2656-4

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

@article{2feb0a48bdf54dfc8cc9e9f979f6dc27,

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

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, {S. 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.}",

note = "Funding Information: Funding This work was supported by NIDDK R01 2 DK078616 and NIDDK K24 DK080140 to J. B. Meigs, a Doris Duke Charitable Foundation Clinical Scientist Development Award to J. C. Florez, RO1 DK066358 to D. W. Bowden, 5RC1HL099911-02 5UC2HL103010-02 and the NHLBI MESA contract N01HC95165-21-0-1 to S. S. Rich.",

year = "2012",

month = nov,

doi = "10.1007/s00125-012-2656-4",

language = "English (US)",

volume = "55",

pages = "2970--2984",

journal = "Diabetologia",

issn = "0012-186X",

publisher = "Springer Verlag",

number = "11",

}

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, S. 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.

N1 - Funding Information: Funding This work was supported by NIDDK R01 2 DK078616 and NIDDK K24 DK080140 to J. B. Meigs, a Doris Duke Charitable Foundation Clinical Scientist Development Award to J. C. Florez, RO1 DK066358 to D. W. Bowden, 5RC1HL099911-02 5UC2HL103010-02 and the NHLBI MESA contract N01HC95165-21-0-1 to S. S. Rich.

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

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