When Is an Endophenotype Useful to Detect Association to a Disease? Exploring the Relationships between Disease Status, Endophenotype and Genetic Polymorphisms

Hum Hered. 2016;81(1):11-25. doi: 10.1159/000446475. Epub 2016 Jul 30.


Objectives: To investigate the conditions and analysis strategies required so that endophenotypes related to a disease help discover genetic variants involved in the disease.

Methods: The association with disease susceptibility variants is examined as a function of the relationships between disease status, endophenotype values and the genotype at another disease or endophenotype susceptibility locus assumed to be previously known, using approximate linear models of allele frequencies as a function of these variables and simulations in the context of family studies when the endophenotype is dichotomous.

Results: Under genetic mechanisms where the risk allele of the tested locus has an effect exclusively in subjects with the endophenotype, the risk allele frequency differences between affected and unaffected subjects are much greater in the subset of subjects with an endophenotype impairment than in those without such an impairment, and power gains are obtained when testing the association under a joint disease-endophenotype model, both with two-locus or single-locus tests. However, with moderate main effect on the risk of disease or endophenotype impairment, testing directly the association between risk allele and disease or endophenotype is more powerful than testing under a joint disease-endophenotype model.

Conclusions: Joint modeling of disease and endophenotype should be used only in parallel with standard disease association testing.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Computer Simulation
  • Endophenotypes*
  • Female
  • Gene Frequency
  • Genetic Predisposition to Disease*
  • Health Status
  • Humans
  • Male
  • Models, Genetic
  • Models, Statistical
  • Polymorphism, Genetic*