Skip to main content
NCBI home page
American Journal of Human Genetics logoLink to American Journal of Human Genetics
. 1984 Jan;36(1):197–211.

Detection of genetic heterogeneity among pedigrees through complex segregation analysis: an application to hypercholesterolemia.

P P Moll, T D Berry, W H Weidman, R Ellefson, H Gordon, B A Kottke
PMCID: PMC1684405  PMID: 6607671

Abstract

Several methods for investigating genetic heterogeneity for extreme levels of a quantitative trait with hypothesized multiple genetic etiologies require a priori stratification of families and/or identification of distinct phenotypes among affected individuals. We present a statistical approach for detecting genetic heterogeneity that does not rely on either a priori stratification or discrete disease phenotypes. Complex segregation analysis was applied to total serum cholesterol measurements in 709 relatives of 98 healthy index cases selected from 3,666 school children surveyed for lipid levels in Rochester, Minnesota. Thirty-three of the index cases and 109 relatives had hypercholesterolemia (cholesterol levels greater than the 95th percentile for their age and sex). Through application of the mixed genetic model and then estimation of conditional probabilities for having the mutant allele at the major locus, genetic heterogeneity for hypercholesterolemia was indicated. In three of 70 pedigrees with one or more hypercholesterolemics, there is strong evidence for segregation at a major locus. In the remaining pedigrees, only polygene variation and/or environmental variation are associated with cholesterol variability. Grandparents in the three pedigrees that were segregating at the major locus had the highest rates of death due to coronary heart disease. This study establishes that the mixed model has the potential to identify pedigrees with different genetic etiologies for variability in quantitative traits.

Full text

PDF
197

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Barbosa J., Chern M. M., Anderson V. E., Noreen H., Johnson S., Reinsmoen N., McCarty R., King R., Greenberg L. Linkage analysis between the major histocompatibility system and insulin-dependent diabetes in families with patients in two consecutive generations. J Clin Invest. 1980 Mar;65(3):592–601. doi: 10.1172/JCI109704. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Barbosa J., Chern M. M., Noreen H., Anderson V. E. Analysis of linkage between the major histocompatibility system and juvenile, insulin-dependent diabetes in multiplex families. Reanalysis of data. J Clin Invest. 1978 Aug;62(2):492–495. doi: 10.1172/JCI109151. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Barbosa J., King R., Noreen H., Yunis E. J. The histocompatibility system in juvenile, insulin-dependent diabetic multiplex kindreds. J Clin Invest. 1977 Nov;60(5):989–998. doi: 10.1172/JCI108879. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Beisiegel U., Schneider W. J., Goldstein J. L., Anderson R. G., Brown M. S. Monoclonal antibodies to the low density lipoprotein receptor as probes for study of receptor-mediated endocytosis and the genetics of familial hypercholesterolemia. J Biol Chem. 1981 Nov 25;256(22):11923–11931. [PubMed] [Google Scholar]
  5. Bucher K. D., Schrott H. G., Clarke W. R., Lauer R. M. The Muscatine Cholesterol Family Study: distribution of cholesterol levels within families of probands with high, low and middle cholesterol levels. J Chronic Dis. 1982;35(5):385–400. doi: 10.1016/0021-9681(82)90009-1. [DOI] [PubMed] [Google Scholar]
  6. Childs B., Der Kaloustian V. M. Genetic heterogeneity. N Engl J Med. 1968 Dec 5;279(23):1267–concl. doi: 10.1056/NEJM196812052792306. [DOI] [PubMed] [Google Scholar]
  7. Cloninger C. R., Bohman M., Sigvardsson S. Inheritance of alcohol abuse. Cross-fostering analysis of adopted men. Arch Gen Psychiatry. 1981 Aug;38(8):861–868. doi: 10.1001/archpsyc.1981.01780330019001. [DOI] [PubMed] [Google Scholar]
  8. Ellefson R. D., Elveback L. R., Hodgson P. A., Weidman W. H. Cholesterol and triglycerides in serum lipoproteins of young persons in Rochester, Minnesota. Mayo Clin Proc. 1978 May;53(5):307–320. [PubMed] [Google Scholar]
  9. Elston R. C., Namboodiri K. K., Glueck C. J., Fallat R., Tsang R., Leuba V. Study of the genetic transmission of hypercholesterolemia and hypertriglyceridemia in a 195 member kindred. Ann Hum Genet. 1975 Jul;39(1):67–87. doi: 10.1111/j.1469-1809.1975.tb00109.x. [DOI] [PubMed] [Google Scholar]
  10. Elston R. C., Namboodiri K. K., Go R. C., Siervogel R. M., Glueck C. J. Probable linkage between essential familial hypercholesterolemia and third complement component (C3). Birth Defects Orig Artic Ser. 1976;12(7):294–297. [PubMed] [Google Scholar]
  11. Elston R. C., Stewart J. A general model for the genetic analysis of pedigree data. Hum Hered. 1971;21(6):523–542. doi: 10.1159/000152448. [DOI] [PubMed] [Google Scholar]
  12. Harris H. Genetic heterogeneity in inherited disease. J Clin Pathol Suppl (R Coll Pathol) 1974;8:32–37. [PMC free article] [PubMed] [Google Scholar]
  13. Hasstedt S. J. A mixed-model likelihood approximation on large pedigrees. Comput Biomed Res. 1982 Jun;15(3):295–307. doi: 10.1016/0010-4809(82)90064-7. [DOI] [PubMed] [Google Scholar]
  14. Hodge S. E., Rotter J. I., Lange K. L. A three-allele model for heterogeneity of juvenile onset insulin-dependent diabetes. Ann Hum Genet. 1980 May;43(4):399–409. doi: 10.1111/j.1469-1809.1980.tb01573.x. [DOI] [PubMed] [Google Scholar]
  15. Iselius L. Analysis of family resemblance for lipids and lipoproteins. Clin Genet. 1979 Apr;15(4):300–306. doi: 10.1111/j.1399-0004.1979.tb01738.x. [DOI] [PubMed] [Google Scholar]
  16. Moll P. P., Powsner R., Sing C. F. Analysis of genetic and environmental sources of variation in serum cholesterol in Tecumseh, Michigan. V. Variance components estimated from pedigrees. Ann Hum Genet. 1979 Jan;42(3):343–354. doi: 10.1111/j.1469-1809.1979.tb00668.x. [DOI] [PubMed] [Google Scholar]
  17. Moll P. P., Sing C. F., Weidman W. H., Gordon H., Ellefson R. D., Hodgson P. A., Kottke B. A. Total cholesterol and lipoproteins in school children: prediction of coronary heart disease in adult relatives. Circulation. 1983 Jan;67(1):127–134. doi: 10.1161/01.cir.67.1.127. [DOI] [PubMed] [Google Scholar]
  18. Morton N. E., Gulbrandsen C. L., Rhoads G. G., Kagan A., Lew R. Major loci for lipoprotein concentrations. Am J Hum Genet. 1978 Nov;30(6):583–589. [PMC free article] [PubMed] [Google Scholar]
  19. Morton N. E., MacLean C. J. Analysis of family resemblance. 3. Complex segregation of quantitative traits. Am J Hum Genet. 1974 Jul;26(4):489–503. [PMC free article] [PubMed] [Google Scholar]
  20. Ott J., Schrott H. G., Goldstein J. L., Hazzard W. R., Allen F. H., Jr, Falk C. T., Motulsky A. G. Linkage studies in a large kindred with familial hypercholesterolemia. Am J Hum Genet. 1974 Sep;26(5):598–603. [PMC free article] [PubMed] [Google Scholar]
  21. Rao D. C., Morton N. E., Gulbrandsen C. L., Rhoads G. G., Kagan A., Yee S. Cultural and biological determinants of lipoprotein concentrations. Ann Hum Genet. 1979 May;42(4):467–477. doi: 10.1111/j.1469-1809.1979.tb00680.x. [DOI] [PubMed] [Google Scholar]
  22. Schneider W. J., Beisiegel U., Goldstein J. L., Brown M. S. Purification of the low density lipoprotein receptor, an acidic glycoprotein of 164,000 molecular weight. J Biol Chem. 1982 Mar 10;257(5):2664–2673. [PubMed] [Google Scholar]
  23. Schrott H. G., Goldstein J. L., Hazzard W. R., McGoodwin M. M., Motulsky A. G. Familial hypercholesterolemia in a large indred. Evidence for a monogenic mechanism. Ann Intern Med. 1972 May;76(5):711–720. doi: 10.7326/0003-4819-76-5-711. [DOI] [PubMed] [Google Scholar]
  24. Simpson J. M., Brennan P. J., McGilchrist C. A., Blacket R. B. Estimation of environmental and genetic components of quantitative traits with application to serum cholesterol levels. Am J Hum Genet. 1981 Mar;33(2):293–299. [PMC free article] [PubMed] [Google Scholar]
  25. Sing C. F., Orr J. D. Analysis of genetic and environmental sources of variation in serum cholesterol in Tecumseh, Michigan. III. Identification of genetic effects using 12 polymorphic genetic blood marker systems. Am J Hum Genet. 1976 Sep;28(5):453–464. [PMC free article] [PubMed] [Google Scholar]
  26. Sing C. F., Orr J. D. Analysis of genetic and environmental sources of variation in serum cholesterol in Tecumseh, Michigan. IV. Separation of polygene from common environment effects. Am J Hum Genet. 1978 Sep;30(5):491–504. [PMC free article] [PubMed] [Google Scholar]
  27. Smith C. Statistical resolution of genetic heterogeneity in familial disease. Ann Hum Genet. 1976 Jan;39(3):281–291. doi: 10.1111/j.1469-1809.1976.tb00132.x. [DOI] [PubMed] [Google Scholar]
  28. Weisgraber K. H., Rall S. C., Jr, Mahley R. W. Human E apoprotein heterogeneity. Cysteine-arginine interchanges in the amino acid sequence of the apo-E isoforms. J Biol Chem. 1981 Sep 10;256(17):9077–9083. [PubMed] [Google Scholar]
  29. Williams W. R., Lalouel J. M. Complex segregation analysis of hyperlipidemia in a Seattle sample. Hum Hered. 1982;32(1):24–36. doi: 10.1159/000153254. [DOI] [PubMed] [Google Scholar]

Articles from American Journal of Human Genetics are provided here courtesy of American Society of Human Genetics

RESOURCES