, Volume 37, Issue 12, pp 1231–1240 | Cite as

Segregation analysis of NIDDM in Caucasian families

  • J. T. E. Cook
  • D. C. Shields
  • R. C. L. Page
  • J. C. Levy
  • A. T. Hattersley
  • J. A. G. Shaw
  • H. A. W. Neil
  • J. S. Wainscoat
  • R. C. Turner


Non-insulin-dependent diabetes mellitus (NIDDM) has a substantial genetic component, but the mode of inheritance and the molecular basis are unknown. We have undertaken segregation analysis of NIDDM after studying 247 subjects in 59 Caucasian nuclear pedigrees ascertained without regard to family history of the disorder. The analyses were performed using POINTER and COMDS, which are computer programs which apply statistical models to the data. POINTER analysis was performed defining the phenotype as a presence or absence of hyperglycaemia. Among single locus hypotheses, the analyses rejected a recessive model and favoured a dominant model, but could not statistically show that this fitted better than a mixed model (a single locus against a polygenic background) or a polygenic model. COMDS analysis assumed a continuum of hyperglycaemia from normality to NIDDM, classified family members into a series of diathesis classes with increasing plasma glucose levels and compared the distribution with that found by screening the normal population. This analysis improved the likelihood of a dominant single locus model and suggested a gene frequency of 7.4%. It raised the possibility of a second locus, but cannot identify or exclude a polygenic model. In conclusion, two types of segregation analyses rejected a recessive model and favoured a dominant model of inheritance, although they could not statistically show that this fitted better than the polygenic model. The results raised the possibility of a common dominant gene with incomplete penetrance, but genetic analysis of NIDDM needs to take into account the likelihood of polygenic inheritance with genetic heterogeneity.

Key words

Non-insulin-dependent diabetes mellitus genetic epidemiology genetic linkage 



Maturity onset diabetes of the young


insulin-dependent diabetes mellitus


non-insulin-dependent diabetes mellitus


fasting plasma glucose


Akaike Information criterion


  1. 1.
    Barnett AH, Eff C, Leslie RDG, Pyke DA (1981) Diabetes in identical twins: a study of 200 pairs. Diabetologia 20: 87–93PubMedGoogle Scholar
  2. 2.
    Newman B, Selby JV, King MC, Slemenda C, Fabsitz R, Friedman GD (1987) Concordance for type 2 (non-insulin-dependent) diabetes mellitus in male twins. Diabetologia 30: 763–768CrossRefPubMedGoogle Scholar
  3. 3.
    Zimmet P, Whitehouse S (1978) Bimodality of fasting and two hour glucose tolerance distributions in a Micronesian population. Diabetes 27: 793–800PubMedGoogle Scholar
  4. 4.
    Rushforth NB, Bennett PH, Steinberg AG, Burch TA, Miller M (1971) Diabetes in the Pima Indians; evidence of bimodality in glucose tolerance distributions. Diabetes 20: 756–765PubMedGoogle Scholar
  5. 5.
    Raper LR, Taylor R, Zimmet P, Milne B, Balkan B (1984) Bimodality in glucose tolerance distributions in the urban Polynesian population of Western Samoa. Diabetes Res 1: 19–26PubMedGoogle Scholar
  6. 6.
    Unger RH, Grundy S (1985) Hyperglycaemia as an inducer as well as a consequence of impaired islet cell function and insulin resistance: implications for the management of diabetes. Diabetologia 28: 119–121CrossRefPubMedGoogle Scholar
  7. 7.
    Thompson GS (1965) Genetic factors in diabetes mellitus studied by the oral glucose tolerance test. J Med Genet 2: 221–226PubMedGoogle Scholar
  8. 8.
    Tillil H, Richter K, Kobberling J (1985) Bimodal distribution of the two-hour blood glucose value during OGTT among first-degree relatives of type 2 diabetics in a Caucasoid population. Diabetes Res Clin Pract 1 [Suppl 1]: S560 (Abstract)Google Scholar
  9. 9.
    Tattersall RB (1974) Mild familial diabetes with dominant inheritance. Q J Med 43: 339–357PubMedGoogle Scholar
  10. 10.
    Pincus G, White P (1933) On the inheritance of diabetes mellitus. 1. An analysis of 675 family histories. Am J Med Sci 186: 1–14Google Scholar
  11. 11.
    Nillsson SE (1964) On the heredity of diabetes mellitus and its interrelationship with some other diseases. Acta Genetica 14: 97Google Scholar
  12. 12.
    Thompson MW, Watson EM (1952) The inheritance of diabetes mellitus. An analysis of the family histories of 1631 diabetics. Diabetes 1: 268–275PubMedGoogle Scholar
  13. 13.
    Steinberg AG (1961) Heredity in diabetes mellitus. Diabetes 10: 269–274Google Scholar
  14. 14.
    Falconer DS, Duncan LJP, Smith C (1971) A statistical and genetic study of diabetes. Ann Hum Genet 34: 347–367PubMedGoogle Scholar
  15. 15.
    Kobberling J, Tillil H (1982) Empirical risk figures for the first-degree relatives of non-insulin-dependent diabetics. In: Kobberling J, Tattersall R (eds) The genetics of diabetes mellitus. Academic Press, London, pp 201–209Google Scholar
  16. 16.
    Cook JTE, Hattersley AT, Levy JC, Patel P, Wainscoat JS, Hockaday TDR, Turner RC (1993) The distribution of type 2 diabetes in nuclear families. Diabetes 42: 106–112PubMedGoogle Scholar
  17. 17.
    Hosker JP, Matthews DR, Rudenski AS, Burnett MA, Darling P, Bown EG, Turner RC (1985) Continuous infusion of glucose with model assessment: Measurement of insulin resistance and Beta-cell function in man. Diabetologia 28: 401–411CrossRefPubMedGoogle Scholar
  18. 18.
    Metropolitan Life Insurance Company (1959) National weights standards for men and women. Stat Bull Metropol Life Insurance Company 40: 1–4Google Scholar
  19. 19.
    Neil HAW, Gatling W, Mather HM, Thompson AV, Thorogood M, Fowler GH, Hill RD, Mann JI (1987) The Oxford Community Diabetes Study: Evidence for an increase in the prevalence of known diabetes in Great Britain. Diabetic Medicine 4: 539–543PubMedGoogle Scholar
  20. 20.
    Welborn TA, Glatthaar C, Whittall D, Bennett S (1989) An estimate of diabetes prevalence from a national population sample: a male excess. Med J Aust 150: 78–81PubMedGoogle Scholar
  21. 21.
    Neil HAWN, Mant D, Jones L, Morgan B, Mann JI (1990) Lipid screening: is it enough to measure total cholesterol concentration? BMJ 301: 584–587PubMedGoogle Scholar
  22. 22.
    Hammersley MS, Levy JC, Volpicelli G, Barrow B, Turner RC (1992) Assessment of impaired glucose tolerance and beta-cell function with a continuous infusion of glucose test and an oral glucose tolerance test. Diabet Med 9 [Suppl 1]: P17 (Abstract)Google Scholar
  23. 23.
    WHO Technical Report Series (1985) No 727 GenevaGoogle Scholar
  24. 24.
    Harris MI, Hadden WC, Knowler WC, Bennett PH (1987) Prevalence of diabetes and impaired glucose tolerance and plasma glucose levels in U.S. population aged 20–74 yr. Diabetes 36: 523–534PubMedGoogle Scholar
  25. 25.
    Lalouel JM, Morton NE (1981) Complex segregation analysis with pointers. Hum Hered 31: 312–321PubMedGoogle Scholar
  26. 26.
    Morton NE, Shields DC, Collins A (1991) Genetic epidemiology of complex genotypes. Ann Hum Genet 55: 301–314PubMedGoogle Scholar
  27. 27.
    Lalouel JM, Le Mignon L, Simon M, Fauchet R, Bourel M, Rao DC, Morton NE (1985) Genetic analysis of idiopathic hemochromatosis using both qualitative (disease status) and quantitative (serum iron) information. Am J Hum Genet 37: 700–718PubMedGoogle Scholar
  28. 28.
    Iselius L, Morton NE (1991) Transmission probabilities are not correctly implemented in the computer program POINTER. Am J Hum Genet 49: 459Google Scholar
  29. 29.
    Akaike H (1973) Information theory and an extension of the maximum likelihood principle. In: Petrov BN, Craki F (eds) Proceedings of the 2nd International Symposium of Information theory. Budapest, Academai Kiado, pp 267–283Google Scholar
  30. 30.
    Akaike H (1987) Factor analysis and AIC. Psychometrika 52: 317–332Google Scholar
  31. 31.
    O'Rahilly S, Spivey RS, Holman RR, Nugent Z, Clark A, Turner RC (1987) Type 2 diabetes of early onset: a distinct clinical and genetic syndrome? Br J Med 294: 923–928Google Scholar
  32. 32.
    Baird JD (1982) Is obesity a factor in the aetiology of noninsulin-dependent diabetes? In: Kobberling J, Tattersall R (eds) The genetics of diabetes mellitus. Academic Press, London, pp 233–241Google Scholar
  33. 33.
    Panzram G (1987) Mortality and survival in type 2 (non-insulin-dependent) diabetes mellitus. Diabetologia 30: 123–131CrossRefPubMedGoogle Scholar
  34. 34.
    Jarrett RJ, Keen H, Fuller JH, McCartney M (1979) Worsening to diabetes in men with impaired glucose tolerance (“borderline diabetes“). Diabetologia 16: 25–30PubMedGoogle Scholar
  35. 35.
    Keen H, Jarrett RJ, McCartney P (1982) The ten-year follow-up of the Bedford survey (1962–1972): glucose tolerance and diabetes. Diabetologia 22: 73–78CrossRefPubMedGoogle Scholar
  36. 36.
    Sartor G, Schersten B, Carlstrom S, Melander A, Norden A, Persson G (1980) Ten-year follow-up of subjects with impaired glucose tolerance: prevention of diabetes by tolbutamide and diet regulation. Diabetes 29: 41–49PubMedGoogle Scholar
  37. 37.
    Charles MA, Fontbonne A, Thibult N, Warnet J-M, Rosselin GE, Eschwege E (1991) Risk factors for type 2 diabetes in a white population: Paris prospective study. Diabetes 40: 796–799PubMedGoogle Scholar
  38. 38.
    Shields DC, Ratanachaiyavong S, McGregor A, Collins A, Morton NE (1994) Combined segregation and linkage analysis of Graves' disease with a thyroid antibody diathesis. Am J Hum Genet 55: 540–554PubMedGoogle Scholar
  39. 39.
    Sham PC, Morton NE, Muir WJ, et al. (1994) Segregation analysis of complex phenotypes: an application to schizophrenia and auditory P300 latency. Psychiatric Genetics 4: 29–38PubMedGoogle Scholar
  40. 40.
    Cooke AM, Fitzgerald MG, Malins JM, Pyke DA (1966) Diabetes in children of diabetic couples. BMJ II: 674–676Google Scholar
  41. 41.
    Kahn CB, Soeldner JS, Gleason RE, Rojas L, Camerini-Davalos RA, Marble A (1969) Clinical and chemical diabetes in the offspring of diabetic couples. N Engl J Med 281: 343–346PubMedGoogle Scholar
  42. 42.
    Tattersall R, Fajans SS (1975) Diabetes and carbohydrate intolerance in 199 offspring of 37 conjugal diabetic parents. Diabetes 24: 452–462PubMedGoogle Scholar
  43. 43.
    Ganda OP, Soeldner SS (1977) Genetic, acquired and related factors in the aetiology of diabetes mellitus. Arch Intern Med 137: 461–469CrossRefPubMedGoogle Scholar
  44. 44.
    Kadowaki T, Kadowaki H, Rechler MM, Serrano-Ris M, Roth J, Gorden P, Tatlor SI (1990) Five mutant alleles of the insulin receptor gene in patients with genetic forms of insulin resistance. J Clin Invest 86: 254–264PubMedGoogle Scholar
  45. 45.
    Cook JTE, Patel P, Clark A et al. (1991) Non-linkage of the islet amyloid polypeptide gene with type 2 diabetes. Diabetologia 34: 103–108PubMedGoogle Scholar
  46. 46.
    Cook JTE, Hattersley AT, Christopher P et al. (1992) Linkage analysis of glucokinase gene with NIDDM in Caucasian pedigrees. Diabetes 41: 1496–1500PubMedGoogle Scholar
  47. 47.
    Cook JTE, Page RCL, O'Rahilly S et al. (1992) The availability of NIDDM families for the detection of diabetes susceptibility genes. Diabetes 1993; 42: 1536–1543Google Scholar
  48. 48.
    Froguel PH, Vaxilaire M, Sun F (1992) Close linkage of glucokinase locus on chromosome 7p to early-onset non-insulin dependent diabetes mellitus. Nature 356: 162–164CrossRefPubMedGoogle Scholar
  49. 49.
    Hattersley AT, Turner RC, Permutt MA (1992) Linkage of type 2 diabetes to the glucokinase gene. Lancet 339: 1307–1310CrossRefPubMedGoogle Scholar
  50. 50.
    Suarez BK (1983) A sib pair strategy for the use of restriction fragment length polymorphisms to study the mode of transmission of type 2 diabetes. Am J Hum Genet 35: 34–48PubMedGoogle Scholar
  51. 51.
    Weeks DE, Lange K (1988) The affected-pedigree-member method of linkage analysis. Am J Hum Genet 42(2): 315–326PubMedGoogle Scholar
  52. 52.
    Stoffel M, Patel P, Lo Y-MD et al. (1992) Characterization of a missense glucokinase mutation in maturity-onset diabetes of the young (MODY) and mutation screening in late-onset diabetes. Nature Genetics 2: 153–156CrossRefPubMedGoogle Scholar
  53. 53.
    Jeunemaitre X, Soubrier F, Kotelevstev et al. (1992) Molecular basis of human hypertension: role of angiotensin. Cell 71: 169–180CrossRefPubMedGoogle Scholar
  54. 54.
    Saiki RK, Gelfand DH, Stoffel et al. (1988) Primer-directed enzymatic amplification of DNA with a thermostable DNA polymerase. Science 239: 487–491PubMedGoogle Scholar
  55. 55.
    Orita M, Suzuki Y, Sekiya T, Hayashi K (1989) Rapid and sensitive detection of point mutations and DNA polymorphisms using the polymerase chain reaction. Genomics 5: 874–879PubMedGoogle Scholar
  56. 56.
    White MB, Carvalho M, Derse D, O'Brien SJ, Dean M (1992) Detecting single base substitutions as heteroduplex polymorphisms. Genomics 12: 301–306PubMedGoogle Scholar

Copyright information

© Springer-Verlag 1994

Authors and Affiliations

  • J. T. E. Cook
    • 1
  • D. C. Shields
    • 2
  • R. C. L. Page
    • 1
  • J. C. Levy
    • 1
  • A. T. Hattersley
    • 1
  • J. A. G. Shaw
    • 1
  • H. A. W. Neil
    • 3
  • J. S. Wainscoat
    • 4
  • R. C. Turner
    • 1
  1. 1.Diabetes Research LaboratoriesClinical Reader, Radcliffe InfirmaryOxfordUK
  2. 2.CRC Genetic Epidemiology Research Group, Department of Child HealthUniversity of SouthamptonUK
  3. 3.Department of Public Health and Primary CareUniversity of OxfordUK
  4. 4.Department of HaematologyJohn Radcliffe HospitalOxfordUK

Personalised recommendations