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


CONCLUSIONS
The proposed strategy is useful to detect modifier loci conferring susceptibility to a specific phenotype within a broader phenotype.
Centre de recherche de l'institut universitaire en santé mentale de Québec, Université Laval, Québec, Québec, Canada. alexandre.bureau@fmed.ulaval.ca
Alexandre
A
Bureau
Jordie
J
Croteau
Chantal
C
Mérette
Alain
A
Fournier
Yvon C
YC
Chagnon
Marc-André
MA
Roy
Michel
M
Maziade
D000483:Alleles; D001714:Bipolar Disorder / Q000235:genetics*; D019295:Computational Biology / Q000379:methods; D003198:Computer Simulation; D005787:Gene Frequency; D060045:Genes, Modifier; D008040:Genetic Linkage; D056426:Genetic Loci; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006801:Humans; D008126:Lod Score; D008957:Models, Genetic; D010375:Pedigree; D019683:Penetrance; D010641:Phenotype; D011618:Psychotic Disorders / Q000235:genetics*; D012559:Schizophrenia / Q000235:genetics*
D005819:Genetic Markers