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Quantitative trait linkage studies of diabetes-related traits

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Abstract

Genetic linkage methods for diseases with complex inheritance are based on assessment of allele sharing between affected relative pairs, but such methods have low power to detect genes with moderate effects. This may explain the difficulty in replication for many of the putative loci for type 2 diabetes. To enhance power to detect diabetes-susceptibility genes, some investigators have performed quantitative-trait linkage studies for diabetes-related traits, including measures of glycemia, insulin sensitivity, insulin secretion, obesity, lipidemia, and blood pressure. These linkage studies have not provided stronger or more consistent evidence for linkage than studies of diabetes affection status, but have identified several loci that may play an important role in the physiologic processes related to the development of type 2 diabetes.

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References and Recommended Reading

  1. Ghosh S, Schork NJ: Genetic analysis of NIDDM: the study of quantitative traits. Diabetes 1996, 45:1–14.

    Article  PubMed  CAS  Google Scholar 

  2. Bogardus C, Lillioja S: Pima Indians as a model to study the genetics of NIDDM. J Cell Biochem 1992, 48:337–343.

    Article  PubMed  CAS  Google Scholar 

  3. Haseman JK, Elston RC: The investigation of linkage between a quantitative trait and a marker locus. Behav Genet 1972, 1:3–19.

    Article  Google Scholar 

  4. Amos CI: Robust variance-components approach for assessing genetic linkage in pedigrees. Am J Hum Genet 1994, 54:535–543.

    PubMed  CAS  Google Scholar 

  5. Pugh EW, Jaquish CE, Sorant AJM, et al.: Comparison of sibpair and variance-components methods for genomic screening. Genet Epidemiol 1997, 14:867–872.

    Article  PubMed  CAS  Google Scholar 

  6. Morton NE: Significance levels in complex inheritance. Am J Hum Genet 1998, 62:690–697.

    Article  PubMed  CAS  Google Scholar 

  7. Lander E, Kruglyak L: Genetic dissection of complex traits: guidelines for interpreting and reporting linkage results. Nat Genet 1995, 11:241–247.

    Article  PubMed  CAS  Google Scholar 

  8. Stern MP: The search for type 2 diabetes susceptibility genes using whole-genome scans: an epidemiologist's perspective. Diabetes Metab Res Rev 2002, 18:106–113. Provides an excellent review of genome-wide linkage studies for type 2 diabetes.

    Article  PubMed  Google Scholar 

  9. Hanson RL, Knowler WC: Type 2 diabetes mellitus and maturity-onset diabetes of the young. In Analysis of Multifactorial Disease. Edited by Bishop T, Sham P. London: BIOS Scientific Publishers; 2000:131–147. Provides an overall review of genetic studies for type 2 diabetes, including linkage studies.

    Google Scholar 

  10. Hanson RL, Ehm MG, Pettitt DJ, et al.: An autosomal genomic scan for loci linked to type II diabetes mellitus and body-mass index in Pima Indians. Am J Hum Genet 1998, 63:1130–1138.

    Article  PubMed  CAS  Google Scholar 

  11. Elbein SC, Hoffman MD, Teng K, et al.: A genome-wide search for type 2 diabetes susceptibility genes in Utah Caucasians. Diabetes 1999, 48:1175–1182.

    Article  PubMed  CAS  Google Scholar 

  12. Vionnet N, Hani EH, Dupont S, et al.: Genomewide search for type 2 diabetes-susceptibilty genes in French whites: evidence for a novel susceptibility locus for early-onset diabetes on chromosome 3q27-qter and independent replication of a type 2-diabetes locus on chromosome 1q21-q24. Am J Hum Genet 2000, 67:1470–1480.

    Article  PubMed  CAS  Google Scholar 

  13. Wiltshire S, Hattersley AT, Hitman GA, et al.: A genomewide scan for loci predisposing to type 2 diabetes in a UK population (the Diabetes UK Warren 2 Repository): analysis of 573 pedigrees provides independent replication of a susceptibility locus on chromosome 1q. Am J Hum Genet 2001, 69:553–569.

    Article  PubMed  CAS  Google Scholar 

  14. Hsueh WC, St Jean PL, Mitchell BD, et al.: Genome-wide and fine-mapping studies of type 2 diabetes and glucose traits in the Old Order Amish: evidence for a new diabetes locus on chromosome 14q11 and confirmation of a locus on chromosome 1q21-q24. Diabetes 2003, 52:550–557.

    Article  PubMed  CAS  Google Scholar 

  15. Xiang K, Wang Y, Zheng T, et al.: Genome-wide search for type 2 diabetes susceptibility loci in Chinese. Diabetes 2002, 51(suppl 2):A262.

    Google Scholar 

  16. Mori Y, Otabe S, Dina C, et al.: Genome-wide search for type 2 diabetes in Japanese affected sib-pairs confirms susceptibility genes on 3q, 15q and 20q and identifies two new candidate loci on 7p and 11p. Diabetes 2002, 51:1247–1255.

    Article  PubMed  CAS  Google Scholar 

  17. Ghosh S, Watanabe RM, Valle TT, et al.: The Finland-United States Investigation of Non-Insulin Dependent Diabetes Melltitus Genetics (FUSION) Study: I: an autosomal genome scan for genes that predispose to type 2 diabetes. Am J Hum Genet 2000, 67:1174–1185.

    PubMed  CAS  Google Scholar 

  18. Zouali H, Hani EH, Philippi A, et al.: A susceptibility locus for early-onset non-insulin dependent (type 2) diabetes mellitus maps to chromosome 20q, proximal to the phosphoenolpyruvate carboxykinase gene. Hum Mol Genet 1997, 6:1401–1408.

    Article  PubMed  CAS  Google Scholar 

  19. Hamman RF: Genetic and environmental determinants of non-insulin dependent diabetes mellitus (NIDDM). Diabetes Metab Rev 1992, 8:287–338.

    Article  PubMed  CAS  Google Scholar 

  20. Stern MP: Diabetes and cardiovascular disease risk: the common soil hypothesis. Diabetes 1995, 44:369–381.

    Article  PubMed  CAS  Google Scholar 

  21. Meigs JB, Panhuysen CIM, Myers RH, et al.: A genome-wide scan for loci linked to plasma levels of glucose and HbA1c in a community-based sample of Caucasian pedigrees: the Framingham Offspring Study. Diabetes 2002, 51:833–840.

    Article  PubMed  CAS  Google Scholar 

  22. Watanabe RM, Ghosh S, Langefeld CD, et al.: The Finland- United States Investigation of Non-Insulin-Dependent Diabetes Mellitus Genetics (FUSION) Study: II: an autosomal genome scan for diabetes-related quantitative traits. Am J Hum Genet 2000, 67:1186–1200. In this linkage study, insulin secretion and insulin sensitivity were measured by the “minimal model” in a frequently sampled IVGTT.

    PubMed  CAS  Google Scholar 

  23. Stern MP, Duggirala R, Mitchell BD, et al.: Evidence for linkage of regions on chromosomes 6 and 11 to plasma glucose concentrations in Mexican Americans. Genome Res 1996, 6:724–734.

    PubMed  CAS  Google Scholar 

  24. Pratley RE, Thompson DB, Prochazka M, et al.: An autosomal genomic scan for loci linked to prediabetic phenotypes in Pima Indians. J Clin Invest 1998, 101:1757–1764.

    Article  PubMed  CAS  Google Scholar 

  25. Cheng LSC, Davis RC, Raffel RJ, et al.: Coincident linkage of fasting plasma insulin and blood pressure to chromosome 7q in hypertensive Hispanic families. Circulation 2001, 104:1255–1260. In this linkage study, insulin sensitivity was measured by the hyperinsulinemic- euglycemic “clamp.”

    PubMed  CAS  Google Scholar 

  26. Phillips DIW, Clark PM, Hales CN, et al.: Understanding oral glucose tolerance: comparison of glucose or insulin measurements during the oral glucose tolerance test with specific measurements of insulin resistance and insulin secretion. Diabet Med 1993, 11:286–292.

    Article  Google Scholar 

  27. Hanson RL, Pratley RE, Bogardus C, et al.: Evaluation of simple indices of insulin sensitivity and insulin secretion for use in epidemiologic studies. Am J Epidemiol 2000, 151:190–198.

    PubMed  CAS  Google Scholar 

  28. Anderson RL, Hamman RF, Savage PJ, et al.: Exploration of simple insulin sensitivity measures derived from frequently sampled intravenous glucose tolerance (FSIGT) tests. Am J Epidemiol 1995, 142:724–732.

    PubMed  CAS  Google Scholar 

  29. Duggirala R, Blangero J, Almasy L, et al.: A major locus for fasting insulin concentrations and insulin resistance on chromosome 6q with strong pleiotropic effects on obesity-related phenotypes in nondiabetic Mexican Americans. Am J Hum Genet 2001, 68:1149–1164.

    Article  PubMed  CAS  Google Scholar 

  30. Mitchell BD, Cole SA, Hsueh WC, et al.: Linkage of serum insulin concentrations to chromosome 3p in Mexican Americans. Diabetes 2000, 49:513–516.

    Article  PubMed  CAS  Google Scholar 

  31. Kissebah AH, Sonnenberg GE, Myklebust J, et al.: Quantitative trait loci on chromosomes 3 and 17 influence phenotypes of the metabolic syndrome. Proc Natl Acad Sci U S A 2000, 97:14478–14483. This linkage study shows strong evidence for linkage of multiple metabolic traits to a region on chromosome 3q.

    Article  PubMed  CAS  Google Scholar 

  32. Hanson RL, Imperatore G, Narayan KMV, et al.: Family and genetic studies of indices of insulin sensitivity and insulin secretion in Pima Indians. Diabetes Metab Res Rev 2001, 17:296–303.

    Article  PubMed  CAS  Google Scholar 

  33. Deng HW, Deng H, Liu YJ, et al.: A genomewide linkage scan for quantitative-trait loci for obesity phenotypes. Am J Hum Genet 2002, 70:1128–1151.

    Article  Google Scholar 

  34. Wu X, Cooper RS, Borecki I, et al.: A combined analysis of genomewide linkage scans for body mass index from the National Heart Lung and Blood Institute Family Blood Pressure Program. Am J Hum Genet 2002, 70:1247–1256.

    Article  PubMed  CAS  Google Scholar 

  35. Stone S, Abkevich V, Hunt SC, et al.: A major predisposition locus for severe obesity at 4p15-p14. Am J Hum Genet 2002, 70:1459–1468.

    Article  PubMed  CAS  Google Scholar 

  36. Atwood LD, Heard-Costa NL, Cupples LA, et al.: Genomewide linkage analysis of body mass index across 28 years of the Framingham Heart Study. Am J Hum Genet 2002, 71:1044–1050.

    Article  PubMed  CAS  Google Scholar 

  37. Feitosa MF, Borecki IB, Rich SS, et al.: Quantitative-trait loci influencing body-mass index reside on chromosomes 7 and 13: the National Heart Lung and Blood Institute Family Heart Study. Am J Hum Genet 2002, 70:72–82.

    Article  PubMed  CAS  Google Scholar 

  38. Comuzzie AG, Hixson JE, Almasy L, et al.: A major quantitative trait locus determining serum leptin levels and fat mass is located on human chromosome 2. Nat Genet 1997, 15:273–276.

    Article  PubMed  CAS  Google Scholar 

  39. Peacock JM, Arnett DK, Atwood LD, et al.: Genome scan for quantitative trait loci linked to high-density lipoprotein cholesterol: the NHLBI Family Heart Study. Arterioscler Thromb Vasc Biol 2001, 21:1823–1828.

    PubMed  CAS  Google Scholar 

  40. Arya R, Duggirala R, Almasy L, et al.: Linkage of high-density lipoprotein-cholesterol concentrations to a locus on chromosome 9p in Mexican Americans. Nat Genet 2002, 30:102–105.

    Article  PubMed  CAS  Google Scholar 

  41. Duggirala R, Blangero J, Almasy L, et al.: A major susceptibility locus influencing plasma triglyceride concentration is located on chromosome 15q in Mexican Americans. Am J Hum Genet 2000, 66:1237–1245.

    Article  PubMed  CAS  Google Scholar 

  42. Elbein SC, Hasstedt SJ: Quantitative trait linkage analysis of lipid-related traits in familial type 2 diabetes. Diabetes 2002, 51:528–535.

    Article  PubMed  CAS  Google Scholar 

  43. Imperatore G, Knowler WC, Pettitt DJ, et al.: A locus influencing total serum cholesterol on chromosome 19p: results from an autosomal genomic scan of serum lipid concentrations in Pima Indians. Arterioscler Thromb Vasc Biol 2000, 20:2651–2656.

    PubMed  CAS  Google Scholar 

  44. Atwood LD, Samollow PB, Hixson JE, et al.: Genome-wide linkage analysis of blood pressure in Mexican Americans. Genet Epidemiol 2001, 20:373–382.

    Article  PubMed  CAS  Google Scholar 

  45. Allayee H, de Bruin TWA, Dominguez M, et al.: Genome scan for blood pressure in Dutch dyslipidemic families reveals linkage to a locus on chromosome 4p. Hypertension 2001, 38:773–778.

    PubMed  CAS  Google Scholar 

  46. Hunt SC, Ellison C, Atwood LD, et al.: Genome scans for blood pressure and hypertension: the National Heart, Lung and Blood Institute Family Heart Study. Hypertension 2002, 40:1–6.

    Article  PubMed  CAS  Google Scholar 

  47. Levy D, DeStefano AL, Larson MG, et al.: Evidence for a gene influencing blood pressure on chromosome 17: genome scan linkage results for longitudinal blood pressure phenotypes in subjects from the Framingham Heart Study. Hypertension 2000, 36:477–483.

    PubMed  CAS  Google Scholar 

  48. Reaven GM: Role of insulin resistance in human disease. Diabetes 1988, 37:1595–1607.

    Article  PubMed  CAS  Google Scholar 

  49. Ferrannini E, Haffner SM, Mitchell BD, et al.: Hyperinsulinaemia: the key feature of a cardiovascular and metabolic syndrome. Diabetologia 1991, 34:416–422.

    Article  PubMed  CAS  Google Scholar 

  50. Meigs JB, D'Agostino RB, Wilson PWF, et al.: Risk variable clustering in the insulin resistance syndrome: the Framingham Offspring Study. Diabetes 1997, 46:1594–1600.

    Article  PubMed  CAS  Google Scholar 

  51. Arya R, Blangero J, Williams K, et al.: Factors of insulin resistance syndrome-related phenotypes are linked to genetic locations on chromosomes 6 and 7 in nondiabetic Mexican- Americans. Diabetes 2002, 51:841–847.

    Article  PubMed  CAS  Google Scholar 

  52. Hanson RL, Imperatore G, Bennett PH, et al.: Components of the “metabolic syndrome” and incidence of type 2 diabetes. Diabetes 2002, 51:3120–3127.

    Article  PubMed  CAS  Google Scholar 

  53. Lindsay RS, Kobes S, Knowler WC, et al.: Genome-wide linkage analysis assessing parent-of-origin effects in the inheritance of birth weight. Hum Genet 2002, 110:503–509.

    Article  PubMed  CAS  Google Scholar 

  54. Hanson RL, Kobes S, Lindsay RS, et al.: Assessment of parentof- origin effects in linkage analysis of quantitative traits. Am J Hum Genet 2001, 68:951–962.

    Article  PubMed  CAS  Google Scholar 

  55. Lindsay RS, Dabelea D, Roumain J, et al.: Type 2 diabetes and low birth weight: the role of paternal inheritance in the association of low birth weight and diabetes. Diabetes 2000, 49:445–449.

    Article  PubMed  CAS  Google Scholar 

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Hanson, R.L., Knowler, W.C. Quantitative trait linkage studies of diabetes-related traits. Curr Diab Rep 3, 176–183 (2003). https://doi.org/10.1007/s11892-003-0042-9

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