Detection of phenotype modifier genes using two-locus linkage analysis in complex disorders such as major psychosis

Hum Hered. 2012;73(4):195-207. doi: 10.1159/000341392. Epub 2012 Aug 15.


Objective: To increase power to detect modifier loci conferring susceptibility to specific phenotypes such as disease diagnoses which are part of a broader disorder spectrum by jointly modeling a modifier and a broad susceptibility gene and to identify modifier loci conferring specific susceptibility to schizophrenia (SZ) or to bipolar disorder (BP) using the approach.

Methods: We implemented a two-locus linkage analysis model where a gene 1 genotype increases the risk of a broad phenotype and a gene 2 genotype modifies the expression of gene 1 by conferring susceptibility to a specific phenotype.

Results: Compared to a single-locus analysis within the broad phenotype, the proposed approach had greater power to detect the modifier gene 2 (0.96 vs. 0.54 under a simulation scenario including heterogeneity). In a sample of 12 mixed SZ and BP Eastern Quebec kindreds, D8S1110 at 8p22 showed the strongest evidence of linkage to a gene determining a specific phenotype (SZ or BP) among subjects susceptible to major psychosis because of putative genes at 10p13 (D10S245, conditional maximized LOD (cMOD) = 4.20, p = 0.0003) and 3q21-q23 (D3S2418, cMOD = 4.09, p = 0.0005).

Conclusion: The proposed strategy is useful to detect modifier loci conferring susceptibility to a specific phenotype within a broader phenotype.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • Bipolar Disorder / genetics*
  • Computational Biology / methods
  • Computer Simulation
  • Gene Frequency
  • Genes, Modifier*
  • Genetic Linkage*
  • Genetic Loci
  • Genetic Markers
  • Genetic Predisposition to Disease / genetics
  • Humans
  • Lod Score
  • Models, Genetic
  • Pedigree
  • Penetrance
  • Phenotype*
  • Psychotic Disorders / genetics*
  • Schizophrenia / genetics*


  • Genetic Markers