A linkage and family-based association analysis of a potential neurocognitive endophenotype of bipolar disorder.
The identification of the genetic variants underpinning bipolar disorder (BPD) has been impeded by a complex pattern of inheritance characterized by genetic and phenotypic heterogeneity, genetic epistasis, and gene-environment interactions. In this paper two strategies were used to ameliorate these confounding factors. A unique South African sample including 190 individuals of the relatively, reproductively isolated Afrikaner population was assessed with a battery of neuropsychological tests in an attempt to identify a BPD-associated quantitative trait or endophenotype. BPD individuals performed significantly worse than their unaffected relatives on visual and verbal memory tasks, a finding congruent with the literature. Afocused linkage and family-based association study was carried out using this memory-related endophenotype. In the largest 77-strong Afrikaner pedigree significant evidence for linkage was detected on chromosome 22q11, a region previously implicated in BPD. The quantitative transmission disequilibrium tests-based association analysis suggested that functional variants of the DRD4 and MAO-A genes modulate memory-related cognition. We speculate that polymorphisms at these loci may predispose to a subtype of BPD characterized by memory-related deficits.
Savitz
Jonathan
J
Division of Human Genetics, Institute for Infectious Disease and Molecular Medicine, University of Cape Town, South Africa. savitz@mail.nih.gov
van der Merwe
Lize
L
Solms
Mark
M
Ramesar
Rajkumar
R
D001714:Bipolar Disorder / Q000235:genetics*; D002892:Chromosomes, Human, Pair 22; D015331:Cohort Studies; D005190:Family; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D009483:Neuropsychological Tests; D010375:Pedigree; D010641:Phenotype; D019655:Quantitative Trait, Heritable; D013019:South Africa