Evidence of associations between bipolar disorder and the brain-derived neurotrophic factor (BDNF) gene.

OBJECTIVE: Brain-derived neurotrophic factor (BDNF) has important roles in neural cell growth and differentiation. Despite multiple lines of evidence suggesting BDNF as a possible contributor to the pathogenesis of bipolar disorder (BD), the results of genetic association studies have been mixed. We hypothesize that BDNF gene polymorphisms may confer increased susceptibility to BD. METHODS: Using a cohort of multiplex bipolar families, we performed family-based association testing to look for associations between BD and eight single nucleotide polymorphisms (SNPs) from BDNF. RESULTS: We found associations (p < 0.05) between BD and six of the eight SNPs analysed, including two SNPs not previously investigated in association studies. We were able to replicate associations previously found between BD and the Val66Met polymorphism of BDNF (rs6265) and the SNPs rs1519480 and rs12273363. We also found evidence of an association between rs11030107 and BD that was not found in a previous study. CONCLUSIONS: Our results support the hypothesis that some BDNF gene polymorphisms may be contributing factors in the pathogenesis of BD. Our study also adds to the body of evidence associating the functional Val66Met polymorphism of BDNF with BD.

Gender differences in bipolar disorder: age of onset, course, comorbidity, and symptom presentation.

OBJECTIVE: To determine whether men and women with bipolar disorder differ in age of onset, course of illness, number of suicide attempts, comorbidity rates and symptom presentation. METHOD: Data were collected from 211 (121 women; 90 men) adults using the Diagnostic Interview for Genetic Studies, medical records, and additional information gathered from relatives. RESULTS: Most gender comparisons showed no evidence of differences. Nonetheless, more men than women reported mania at the onset of bipolar I disorder. Men also had higher rates of comorbid alcohol abuse/dependence, cannabis abuse/dependence, pathological gambling and conduct disorder. Men were more likely to report 'behavioural problems' and 'being unable to hold a conversation' during mania. Women reported higher rates of comorbid eating disorders, and weight change, appetite change and middle insomnia during depression. CONCLUSIONS: Men and women were generally similar in their symptom presentation, age of onset of bipolar disorder, and in the total number of mood episodes. However, they differed in the type of episode at onset and comorbidity patterns.

Affective disorders in the first-degree relatives of bipolar probands: results from the South Island Bipolar Study.

The current study was performed to document observed rates of affective disorders in the first degree relatives of probands with bipolar I or II disorder; to determine whether bipolar II probands have an excess of bipolar II relatives; and to determine whether bipolar probands with a history of one or more suicide attempts have more relatives who have also made suicide attempts. Bipolar probands with positive family histories of affective disorder were recruited from a variety of sources for a study on the molecular genetics of bipolar disorder. Probands and relatives were interviewed with the Diagnostic Interview for Genetic Studies (DIGS) and blood was obtained for DNA extraction and genetic analyses. Among 423 first-degree adult relatives of 153 bipolar probands, 7% (29) had bipolar I disorder, 7% had bipolar II disorder, and 7% had bipolar not otherwise specified (NOS) disorder, making 21% of relatives with any bipolar disorder. A further 42% of relatives had a depressive disorder and only 38% had no affective disorder. A suicide attempt by a proband was not associated with any increase in suicide attempts by relatives. We conclude that while unipolar depressive disorders are the most common affective disorders in the first-degree relatives of bipolar probands, extension of the bipolar phenotype to include bipolar spectrum disorders results in 21% of relatives having any bipolar disorder.

Bipolar-panic disorder comorbidity within bipolar disorder families: a study of siblings.

OBJECTIVES: Although anxiety disorders often co-occur with bipolar disorder in clinical settings, relatively few studies of bipolar disorder have looked specifically at panic comorbidity. This report examines lifetime panic comorbidity within a sample of families with a history of bipolar disorder. METHODS: One hundred and nine probands with bipolar disorder and their 226 siblings were interviewed as part of a family-genetic study. Logistic regression was used to model bipolar disorder as a predictor of comorbid panic in those with affective disorder, with age at interview and gender included as covariates. RESULTS: The percentage with panic attacks was low in those without affective disorder (3%) compared with those with unipolar depression (22%) or bipolar disorder (32%). Panic disorder was found only in those with affective disorder (6% for unipolar, 16% for bipolar). When bipolar disorder and unipolar disorder were compared, controlling for age and sex, having bipolar disorder was associated with panic disorder (OR = 3.0, 95% CI = 1.1, 7.8) and any panic symptoms (OR = 2.0, CI = 1.0,3.8) and more weakly with the combination of panic disorder and recurrent attacks (OR = 1.8, CI = 0.9, 3.5). CONCLUSIONS: The absence of panic disorder and the low prevalence of any panic symptoms in those without bipolar or unipolar disorder suggest that panic is associated primarily with affective disorder within families with a history of bipolar disorder. Furthermore, panic disorder and symptoms are more common in bipolar disorder than in unipolar disorder in these families.

Association of a duplicated repeat polymorphism in the 5'-untranslated region of the DRD4 gene with novelty seeking.

Novelty Seeking (NS) is a human personality trait in which impulsive, exploratory, and thrill-seeking behaviors are displayed. Dopaminergic genes have been prime candidates in the search for the genetic factors underlying NS because of the central role that dopamine plays in the brain's reward system. We have investigated whether there is an association between a polymorphic 120 base pairs (bp) repeat that is located in the 5'-untranslated region of the dopamine D4 receptor gene (DRD4) and NS. We genotyped four separate groups from psychiatric clinical studies for the repeat polymorphism. There were significant associations with NS in the groups of bipolar (P = 0.01) and alcoholic (P = 0.006) families containing 267 and 172 subjects, respectively. Subjects who were homozygous for the single-copy allele (SS genotype) had higher mean NS scores. This trend was also observed in the two other studies that contained unrelated subjects diagnosed with depression (N = 143 and N = 148) but the associations between DRD4 duplication genotype and NS were not significant in these groups. In the data combined from all four clinical groups those genotyped as SS had higher mean scores for all four NS subscales with significant associations for impulsivity (P = 0.0006), extravagance (P = 0.04), disorderliness (P = 0.02), and total NS (P = 0.0003). However, given the low frequency of the single-copy allele, this polymorphism would account for only a small proportion of the variance of NS in the population.