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

Alexandre Bureau, Jordie Croteau, Chantal Mrette, Alain Fournier, Yvon C. Chagnon, Marc Andr Roy, Michel Maziade

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Pages (from-to)195-207
Number of pages13
JournalHuman Heredity
Volume73
Issue number4
DOIs
StatePublished - Sep 2012

Keywords

  • Bipolar disorder
  • Parametric linkage analysis
  • Pedigree analysis
  • Phenotype model
  • Schizophrenia

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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