Personality endophenotypes for bipolar affective disorder: a family-based genetic association analysis.
Genetic analyses of complex conditions such as bipolar disorder (BD) may be facilitated by the use of intermediate phenotypes. Various personality traits are overrepresented in people with BD and their unaffected relatives, and may constitute genetically transmitted risk factors or endophenotypes of the illness. In this study, we administered a battery of seven different personality questionnaires comprising 19 subscales to 31 Caucasian BD families (n = 241). Ten of these personality traits showed significant evidence of heritability and were therefore selected as candidate endophenotypes. In addition, a principal components analysis produced two heritable components (negative affect and appetitive drive), which accounted for a considerable proportion of the variance (29% + 12%) and were also used in the analysis. A family-based quantitative association study was carried out using the orthogonal model from the quantitative transmission disequilibrium tests (QTDT) program. Monte Carlo permutations (M = 500), which allow for non-normal data and provide a global P value, corrected for multiple testing, were used to calculate empirical P values for the within-family component of association. The 3' untranslated region repeat polymorphism of the dopamine transporter gene (SLC6A3) was associated with self-directedness (P < 0.0001) and negative affect (P = 0.010). The short allele of the serotonin transporter gene (SLC6A4) promoter polymorphism showed a trend toward association with higher harm avoidance (P = 0.016) and negative affect (P = 0.028). The catechol-o-methyltransferase val158met polymorphism was weakly associated with the personality traits, 'Spirituality' (P = 0.040) and irritable temperament (P = 0.022). Furthermore, the met allele of the brain-derived neurotrophic factor val66met polymorphism was associated with higher hyperthymic temperament scores. We raise the possibility that the 10R allele of the SLC6A3 repeat polymorphism and the short allele of the SLC6A4 promoter variant constitute risk factors for irritable-aggressive and anxious-dysthymic subtypes of BD, respectively.
Savitz
J
J
UCT/MRC Human Genetics Research Unit, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa. savitzj@mail.nih.gov
van der Merwe
L
L
Ramesar
R
R
D000328:Adult; D000368:Aged; D001714:Bipolar Disorder / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D002394:Catechol O-Methyltransferase / Q000235:genetics; D015331:Cohort Studies; D050483:Dopamine Plasma Membrane Transport Proteins / Q000235:genetics; D005190:Family / Q000523:psychology; D005260:Female; D005787:Gene Frequency / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D055106:Genome-Wide Association Study; D006801:Humans; D040582:Inheritance Patterns / Q000235:genetics*; D015810:Linkage Disequilibrium / Q000235:genetics; D008297:Male; D008875:Middle Aged; D010551:Personality / Q000235:genetics*; D010555:Personality Inventory; D010641:Phenotype; D011110:Polymorphism, Genetic / Q000235:genetics; D025341:Principal Component Analysis; D050486:Serotonin Plasma Membrane Transport Proteins / Q000235:genetics; D011795:Surveys and Questionnaires; D013694:Temperament / Q000502:physiology
D050483:Dopamine Plasma Membrane Transport Proteins; C493214:SLC6A3 protein, human; D050486:Serotonin Plasma Membrane Transport Proteins; D002394:Catechol O-Methyltransferase