• We are sorry, but NCBI web applications do not support your browser and may not function properly. More information
Logo of ajhgLink to Publisher's site
Am J Hum Genet. Jul 1999; 65(1): 229–235.
PMCID: PMC1378094

Methods for detection of parent-of-origin effects in genetic studies of case-parents triads.


When affected probands and their biological parents are genotyped at a candidate gene or a marker, the resulting case-parents-triad data enable powerful tests for linkage in the presence of association. When linkage disequilibrium has been detected in such a study, the investigator may wish to look further for possible parent-of-origin effects. If, for example, the transmission/disequilibrium test restricted to fathers is statistically significant, whereas that restricted to mothers is not, the investigator might interpret this as evidence for nonexpression of the maternally derived disease gene-that is, imprinting. This report reviews existing methods for detection of parent-of-origin effects, showing that each can be invalid under certain scenarios. Two new methods are proposed, based on application of likelihood-based inference after stratification on both the parental mating type and the inherited number of copies of the allele under study. If there are no maternal genetic effects expressed prenatally during gestation, the parental-asymmetry test is powerful and provides valid estimation of a parent-of-origin parameter. For diseases for which there could be maternal effects on risk, the parent-of-origin likelihood-ratio test provides a robust alternative. Simulations based on an admixed population demonstrate good operating characteristics for these procedures, under diverse scenarios.

Full Text

The Full Text of this article is available as a PDF (174K).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Falk CT, Rubinstein P. Haplotype relative risks: an easy reliable way to construct a proper control sample for risk calculations. Ann Hum Genet. 1987 Jul;51(Pt 3):227–233. [PubMed]
  • Schaid DJ. Likelihoods and TDT for the case-parents design. Genet Epidemiol. 1999;16(3):250–260. [PubMed]
  • Schaid DJ, Sommer SS. Genotype relative risks: methods for design and analysis of candidate-gene association studies. Am J Hum Genet. 1993 Nov;53(5):1114–1126. [PMC free article] [PubMed]
  • Self SG, Longton G, Kopecky KJ, Liang KY. On estimating HLA/disease association with application to a study of aplastic anemia. Biometrics. 1991 Mar;47(1):53–61. [PubMed]
  • Spielman RS, Ewens WJ. The TDT and other family-based tests for linkage disequilibrium and association. Am J Hum Genet. 1996 Nov;59(5):983–989. [PMC free article] [PubMed]
  • Spielman RS, McGinnis RE, Ewens WJ. Transmission test for linkage disequilibrium: the insulin gene region and insulin-dependent diabetes mellitus (IDDM). Am J Hum Genet. 1993 Mar;52(3):506–516. [PMC free article] [PubMed]
  • Weinberg CR. Allowing for missing parents in genetic studies of case-parent triads. Am J Hum Genet. 1999 Apr;64(4):1186–1193. [PMC free article] [PubMed]
  • Weinberg CR, Wilcox AJ, Lie RT. A log-linear approach to case-parent-triad data: assessing effects of disease genes that act either directly or through maternal effects and that may be subject to parental imprinting. Am J Hum Genet. 1998 Apr;62(4):969–978. [PMC free article] [PubMed]
  • Wilcox AJ, Weinberg CR, Lie RT. Distinguishing the effects of maternal and offspring genes through studies of "case-parent triads". Am J Epidemiol. 1998 Nov 1;148(9):893–901. [PubMed]

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