Investigating the role of BDNF and CCK system genes in suicidality in a familial bipolar cohort.

BACKGROUND: Suicidal behaviour is a phenotype widely associated with psychiatric disorders such as major depressive disorder and bipolar disorder. However, recent evidence indicates that part of the heritability of suicidal behaviour is independent of the heritability of individual psychiatric disorders. This allows investigation into genetic risk factors for suicidal behaviour within a disorder using a candidate gene association approach. METHODS: We used family-based association testing in a cohort of 130 multiplex bipolar pedigrees, comprising 795 individuals, to look for associations between suicidal behaviour and 32 single nucleotide polymorphisms (SNPs) from across the genes brain-derived neurotrophic factor (BDNF), cholecystokinin (CCK) and the cholecystokinin beta-receptor (CCKBR). RESULTS: We found associations (p≤0.05) between suicide attempt and 12 SNPs of CCKBR and five SNPs of BDNF. After correction for multiple testing, seven SNPs of CCKBR remained significantly associated. No association was found between CCK and suicidal behaviour. LIMITATIONS: The study relied on retrospective self-reporting by individuals to determine phenotype, and the sample size was relatively small. CONCLUSIONS: The results of the study support the hypothesis that some CCKBR polymorphisms may contribute to an underlying predisposition towards suicidal behaviour in bipolar disorder.

Cholecystokinin system genes: associations with panic and other psychiatric disorders.

BACKGROUND: The cholecystokinin (CCK) system has long been hypothesised to have a role in the pathogenesis of panic attacks. Previous research into genetic variation within the CCK gene and the genes for its two receptors, CCKAR and CCKBR, has produced mixed results. We aimed to clarify this association by investigating multiple variants within each gene and multiple phenotypes associated with panic that may have confounded the previous studies' findings. METHODS: Variants were selected for the three genes based on HapMap CEU data. Individuals from a family based cohort (n=563) were genotyped for these variations and this data was analysed in FBAT. RESULTS: CCKBR showed the strongest association with panic, having multiple variants with p<0.05 (lowest: p=0.007). In CCKAR, some evidence was found for an association with panic, though further analysis suggested that the co-morbid bipolar-panic phenotype was most strongly associated. No variants in CCK were associated with panic but broader anxiety phenotypes did show associations. LIMITATIONS: Small sample size prevented thorough investigation of phenotypes, particularly pure disorders, and no correction was made for the multiple phenotypes analysed. CONCLUSIONS: Our findings support the involvement of variation in the CCK system, particularly CCKBR, in the pathogenesis of panic. Our data suggest that variation in CCK may be involved in several anxiety phenotypes and CCKAR may be involved in the development of panic co-morbid with bipolar disorder. These latter findings require further investigation and highlight the importance of clearly defined phenotypes when investigating psychiatric genetics.

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.

PCR detectable Y chromosome-specific DNA but no intact Y chromosome-bearing cells in polymyositis biopsies of two women with male offspring.

AIMS: Pregnancy-related and idiopathic adult polymyositis are inflammatory myopathies of unknown aetiology in which CD8 positive T cells are found in close association with the up-regulation of human leukocyte antigen (HLA) class I on affected muscle cells. A similar polymyositis can also occur in patients with chronic graft versus host disease, wherein graft lymphocytes may be involved in the myositis. We investigated whether polymyositis that was temporally related to pregnancy, contained Y chromosome-bearing cells or signals using polymerase chain reaction (PCR) in biopsies of lesional muscle from two women who had given birth to sons. Furthermore, if Y chromosome material was present, we investigated whether it was contained in the intact inflammatory cells (CD8 positive lymphocytes for example), fetal macrophages, or differentiated fetal stem cells engrafted in the lesional skeletal muscle, and thus whether fetal cells played a role in the pathogenesis of the myositis. METHODS: PCR analysis was used for the Y chromosome in lesional tissue and fluorescence in situ hybridisation (FISH) for intact cells carrying the Y chromosome. RESULTS: Small amounts of Y chromosome material were detected on second round PCR in fresh frozen tissue. No Y chromosome-bearing intact cells of lymphocytic, macrophage or muscle lineage were detected. CONCLUSION: Our results suggest that microchimeric fetal cells are not found in the lesional tissue of pregnancy-related polymyositis.