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. 2000 May 2;66(6):1871–1881. doi: 10.1086/302950

Genomewide search for type 2 diabetes susceptibility genes in four American populations.

M G Ehm 1, M C Karnoub 1, H Sakul 1, K Gottschalk 1, D C Holt 1, J L Weber 1, D Vaske 1, D Briley 1, L Briley 1, J Kopf 1, P McMillen 1, Q Nguyen 1, M Reisman 1, E H Lai 1, G Joslyn 1, N S Shepherd 1, C Bell 1, M J Wagner 1, D K Burns 1; American Diabetes Association GENNID Study Group. Genetics of NIDDM1
PMCID: PMC1378057  PMID: 10793009

Abstract

Type 2 diabetes is a serious, genetically influenced disease for which no fully effective treatments are available. Identification of biochemical or regulatory pathways involved in the disease syndrome could lead to innovative therapeutic interventions. One way to identify such pathways is the genetic analysis of families with multiple affected members where disease predisposing genes are likely to be segregating. We undertook a genomewide screen (389-395 microsatellite markers) in samples of 835 white, 591 Mexican American, 229 black, and 128 Japanese American individuals collected as part of the American Diabetes Association's GENNID study. Multipoint nonparametric linkage analyses were performed with diabetes, and diabetes or impaired glucose homeostasis (IH). Linkage to diabetes or IH was detected near markers D5S1404 (map position 77 cM, LOD = 2.80), D12S853 (map position 82 cM, LOD = 2.81) and GATA172D05 (X-chromosome map position 130 cM, LOD = 2.99) in whites, near marker D3S2432 (map position 51 cM, LOD = 3.91) in Mexican Americans, and near marker D10S1412 (map position 14 cM, LOD = 2.39) in African Americans mainly collected in phase 1 of the study. Further analyses showed evidence for interactions between the chromosome 5 locus and region on chromosome 12 containing the MODY 3 gene (map position 132 cM) and between the X-chromosome locus and region near D12S853 (map position 82 cM) in whites. Although these results were not replicated in samples collected in phase 2 of the GENNID study, the region on chromosome 12 was replicated in samples from whites described by Bektas et al. (1999).

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Selected References

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  1. Bektas A., Suprenant M. E., Wogan L. T., Plengvidhya N., Rich S. S., Warram J. H., Krolewski A. S., Doria A. Evidence of a novel type 2 diabetes locus 50 cM centromeric to NIDDM2 on chromosome 12q. Diabetes. 1999 Nov;48(11):2246–2251. doi: 10.2337/diabetes.48.11.2246. [DOI] [PubMed] [Google Scholar]
  2. Bowden D. W., Sale M., Howard T. D., Qadri A., Spray B. J., Rothschild C. B., Akots G., Rich S. S., Freedman B. I. Linkage of genetic markers on human chromosomes 20 and 12 to NIDDM in Caucasian sib pairs with a history of diabetic nephropathy. Diabetes. 1997 May;46(5):882–886. doi: 10.2337/diab.46.5.882. [DOI] [PubMed] [Google Scholar]
  3. Chen J. F., Guo J. H., Moxham C. M., Wang H. Y., Malbon C. C. Conditional, tissue-specific expression of Q205L G alpha i2 in vivo mimics insulin action. J Mol Med (Berl) 1997 Apr;75(4):283–289. doi: 10.1007/s001090050113. [DOI] [PubMed] [Google Scholar]
  4. Cox N. J., Frigge M., Nicolae D. L., Concannon P., Hanis C. L., Bell G. I., Kong A. Loci on chromosomes 2 (NIDDM1) and 15 interact to increase susceptibility to diabetes in Mexican Americans. Nat Genet. 1999 Feb;21(2):213–215. doi: 10.1038/6002. [DOI] [PubMed] [Google Scholar]
  5. Duggirala R., Blangero J., Almasy L., Dyer T. D., Williams K. L., Leach R. J., O'Connell P., Stern M. P. Linkage of type 2 diabetes mellitus and of age at onset to a genetic location on chromosome 10q in Mexican Americans. Am J Hum Genet. 1999 Apr;64(4):1127–1140. doi: 10.1086/302316. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Ehm M., Wagner M. A test statistic to detect errors in sib-pair relationships. Am J Hum Genet. 1998 Jan;62(1):181–188. doi: 10.1086/301668. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Elbein S. C., Hoffman M. D., Teng K., Leppert M. F., Hasstedt S. J. A genome-wide search for type 2 diabetes susceptibility genes in Utah Caucasians. Diabetes. 1999 May;48(5):1175–1182. doi: 10.2337/diabetes.48.5.1175. [DOI] [PubMed] [Google Scholar]
  8. Froguel P., Zouali H., Vionnet N., Velho G., Vaxillaire M., Sun F., Lesage S., Stoffel M., Takeda J., Passa P. Familial hyperglycemia due to mutations in glucokinase. Definition of a subtype of diabetes mellitus. N Engl J Med. 1993 Mar 11;328(10):697–702. doi: 10.1056/NEJM199303113281005. [DOI] [PubMed] [Google Scholar]
  9. Ghosh S., Watanabe R. M., Hauser E. R., Valle T., Magnuson V. L., Erdos M. R., Langefeld C. D., Balow J., Jr, Ally D. S., Kohtamaki K. Type 2 diabetes: evidence for linkage on chromosome 20 in 716 Finnish affected sib pairs. Proc Natl Acad Sci U S A. 1999 Mar 2;96(5):2198–2203. doi: 10.1073/pnas.96.5.2198. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Hani E. H., Clément K., Velho G., Vionnet N., Hager J., Philippi A., Dina C., Inoue H., Permutt M. A., Basdevant A. Genetic studies of the sulfonylurea receptor gene locus in NIDDM and in morbid obesity among French Caucasians. Diabetes. 1997 Apr;46(4):688–694. doi: 10.2337/diab.46.4.688. [DOI] [PubMed] [Google Scholar]
  11. Hanis C. L., Boerwinkle E., Chakraborty R., Ellsworth D. L., Concannon P., Stirling B., Morrison V. A., Wapelhorst B., Spielman R. S., Gogolin-Ewens K. J. A genome-wide search for human non-insulin-dependent (type 2) diabetes genes reveals a major susceptibility locus on chromosome 2. Nat Genet. 1996 Jun;13(2):161–166. doi: 10.1038/ng0696-161. [DOI] [PubMed] [Google Scholar]
  12. Hansen T., Andersen C. B., Echwald S. M., Urhammer S. A., Clausen J. O., Vestergaard H., Owens D., Hansen L., Pedersen O. Identification of a common amino acid polymorphism in the p85alpha regulatory subunit of phosphatidylinositol 3-kinase: effects on glucose disappearance constant, glucose effectiveness, and the insulin sensitivity index. Diabetes. 1997 Mar;46(3):494–501. doi: 10.2337/diab.46.3.494. [DOI] [PubMed] [Google Scholar]
  13. Hanson R. L., Ehm M. G., Pettitt D. J., Prochazka M., Thompson D. B., Timberlake D., Foroud T., Kobes S., Baier L., Burns D. K. An autosomal genomic scan for loci linked to type II diabetes mellitus and body-mass index in Pima Indians. Am J Hum Genet. 1998 Oct;63(4):1130–1138. doi: 10.1086/302061. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Kawanishi M., Tamori Y., Masugi J., Mori H., Ito C., Hansen T., Andersen C. B., Pedersen O., Kasuga M. Prevalence of a polymorphism of the phosphatidylinositol 3-kinase p85 alpha regulatory subunit (codon 326 Met-->Ile) in Japanese NIDDM patients. Diabetes Care. 1997 Jun;20(6):1043–1043. doi: 10.2337/diacare.20.6.1043. [DOI] [PubMed] [Google Scholar]
  15. Kong A., Cox N. J. Allele-sharing models: LOD scores and accurate linkage tests. Am J Hum Genet. 1997 Nov;61(5):1179–1188. doi: 10.1086/301592. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Kruglyak L., Daly M. J., Reeve-Daly M. P., Lander E. S. Parametric and nonparametric linkage analysis: a unified multipoint approach. Am J Hum Genet. 1996 Jun;58(6):1347–1363. [PMC free article] [PubMed] [Google Scholar]
  17. Lander E. S., Green P. Construction of multilocus genetic linkage maps in humans. Proc Natl Acad Sci U S A. 1987 Apr;84(8):2363–2367. doi: 10.1073/pnas.84.8.2363. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Lander E., Kruglyak L. Genetic dissection of complex traits: guidelines for interpreting and reporting linkage results. Nat Genet. 1995 Nov;11(3):241–247. doi: 10.1038/ng1195-241. [DOI] [PubMed] [Google Scholar]
  19. Mahtani M. M., Widén E., Lehto M., Thomas J., McCarthy M., Brayer J., Bryant B., Chan G., Daly M., Forsblom C. Mapping of a gene for type 2 diabetes associated with an insulin secretion defect by a genome scan in Finnish families. Nat Genet. 1996 Sep;14(1):90–94. doi: 10.1038/ng0996-90. [DOI] [PubMed] [Google Scholar]
  20. Moxham C. M., Malbon C. C. Insulin action impaired by deficiency of the G-protein subunit G ialpha2. Nature. 1996 Feb 29;379(6568):840–844. doi: 10.1038/379840a0. [DOI] [PubMed] [Google Scholar]
  21. Raffel L. J., Robbins D. C., Norris J. M., Boerwinkle E., DeFronzo R. A., Elbein S. C., Fujimoto W., Hanis C. L., Kahn S. E., Permutt M. A. The GENNID Study. A resource for mapping the genes that cause NIDDM. Diabetes Care. 1996 Aug;19(8):864–872. doi: 10.2337/diacare.19.8.864. [DOI] [PubMed] [Google Scholar]
  22. Rich S. S. Mapping genes in diabetes. Genetic epidemiological perspective. Diabetes. 1990 Nov;39(11):1315–1319. doi: 10.2337/diab.39.11.1315. [DOI] [PubMed] [Google Scholar]
  23. Riggs A. C., Tanizawa Y., Aoki M., Wasson J., Ferrer J., Rabin D. U., Vaxillaire M., Froguel P., Permutt M. A. Characterization of the LIM/homeodomain gene islet-1 and single nucleotide screening in NIDDM. Diabetes. 1995 Jun;44(6):689–694. doi: 10.2337/diab.44.6.689. [DOI] [PubMed] [Google Scholar]
  24. Tanizawa Y., Riggs A. C., Dagogo-Jack S., Vaxillaire M., Froguel P., Liu L., Donis-Keller H., Permutt M. A. Isolation of the human LIM/homeodomain gene islet-1 and identification of a simple sequence repeat polymorphism [corrected]. Diabetes. 1994 Jul;43(7):935–941. doi: 10.2337/diab.43.7.935. [DOI] [PubMed] [Google Scholar]
  25. Terauchi Y., Tsuji Y., Satoh S., Minoura H., Murakami K., Okuno A., Inukai K., Asano T., Kaburagi Y., Ueki K. Increased insulin sensitivity and hypoglycaemia in mice lacking the p85 alpha subunit of phosphoinositide 3-kinase. Nat Genet. 1999 Feb;21(2):230–235. doi: 10.1038/6023. [DOI] [PubMed] [Google Scholar]
  26. Turner R. C., Hattersley A. T., Shaw J. T., Levy J. C. Type II diabetes: clinical aspects of molecular biological studies. Diabetes. 1995 Jan;44(1):1–10. doi: 10.2337/diab.44.1.1. [DOI] [PubMed] [Google Scholar]
  27. Urbanek M., Legro R. S., Driscoll D. A., Azziz R., Ehrmann D. A., Norman R. J., Strauss J. F., 3rd, Spielman R. S., Dunaif A. Thirty-seven candidate genes for polycystic ovary syndrome: strongest evidence for linkage is with follistatin. Proc Natl Acad Sci U S A. 1999 Jul 20;96(15):8573–8578. doi: 10.1073/pnas.96.15.8573. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Yamagata K., Furuta H., Oda N., Kaisaki P. J., Menzel S., Cox N. J., Fajans S. S., Signorini S., Stoffel M., Bell G. I. Mutations in the hepatocyte nuclear factor-4alpha gene in maturity-onset diabetes of the young (MODY1) Nature. 1996 Dec 5;384(6608):458–460. doi: 10.1038/384458a0. [DOI] [PubMed] [Google Scholar]
  29. Yamagata K., Oda N., Kaisaki P. J., Menzel S., Furuta H., Vaxillaire M., Southam L., Cox R. D., Lathrop G. M., Boriraj V. V. Mutations in the hepatocyte nuclear factor-1alpha gene in maturity-onset diabetes of the young (MODY3) Nature. 1996 Dec 5;384(6608):455–458. doi: 10.1038/384455a0. [DOI] [PubMed] [Google Scholar]
  30. Yuan B., Vaske D., Weber J. L., Beck J., Sheffield V. C. Improved set of short-tandem-repeat polymorphisms for screening the human genome. Am J Hum Genet. 1997 Feb;60(2):459–460. [PMC free article] [PubMed] [Google Scholar]

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