Bente Bennike

The BDNF Val66Met polymorphism: Relation to familiar risk of affective disorder, BDNF levels and salivary cortisol

BACKGROUND Brain-derived neurotrophic factor (BDNF) and the hypothalamic-pituitary-adrenal (HPA) axis are considered to play an important role in the pathophysiology of affective disorders. The aim of the present study was to investigate whether the BDNF Val66Met polymorphism is associated with a familiar risk of affective disorder and whether these genotypes affect whole blood BDNF level and salivary cortisol. METHOD In a high-risk study, healthy monozygotic and dizygotic twins with and without a co-twin (high- and low-risk twins, respectively) history of affective disorder were identified through nationwide registers. RESULTS Familiar predisposition to unipolar and bipolar disorder was not associated with any specific genotype pattern of the BDNF Val66Met polymorphism, not in this sample of 124 val/val, 58 val/met and 8 met/met individuals. However, the combination of having a high familiar risk of affective disorder and the met allele was associated with a higher whole blood BDNF (p=0.02) and a higher evening cortisol level (p=0.01), but not with awakening cortisol. CONCLUSION Individuals at high risk of affective disorders and who are carriers of the met allele of the Val66Met polymorphism may present with an enhanced stress response. The presence of a specific genotype alone may not enhance the risk of developing an affective episode. Rather, the altered stress response may be expressed only in combination with other risk variants through interactions with the environment.

Platelet serotonin transporters and the transporter gene in control subjects, unipolar patients and bipolar patients

Objective: The purpose of the present study was to relate the number of platelet serotonin transporters in unipolar and bipolar patients and in control subjects to two polymorphisms in the serotonin transporter gene: a VNTR in intron 2 and a deletion/insertion in the promoter region.

Salivary cortisol in unaffected twins discordant for affective disorder.

Dysfunction in the hypothalamic-pituitary-adrenal (HPA) axis has been proposed as a biological endophenotype for affective disorders. In the present study the hypothesis that a high genetic liability to affective disorder is associated with higher cortisol levels was tested in a cross-sectional high-risk study. Healthy monozygotic (MZ) and dizygotic (DZ) twins with (High-Risk twins) and without (Low-Risk twins) a co-twin history of affective disorder were identified through nationwide registers. Awakening and evening salivary cortisol levels were compared between the 190 High- and Low-Risk twins. The 109 High-Risk twins had significantly higher evening cortisol levels than the 81 Low-Risk MZ twins, also after adjustment for age, sex, and the level of subclinical depressive symptoms. No significant difference was found in awakening cortisol levels between High-Risk and Low-Risk twins. In conclusion, a high genetic liability to affective disorder was associated with a higher evening cortisol level, but not with awakening cortisol level. Future prospective family, high-risk and twin studies are needed to decide whether abnormalities in the HPA axis can be identified as an endophenotype of affective disorder.

The short/long polymorphism in the serotonin transporter gene promoter is not associated with panic disorder in a Scandinavian sample

Several studies have reported an association between thes allele of the 5-HTT gene and anxiety-related person-ality traits in healthy individuals (Lesch et al., 1996;Mazzanti et al., 1998; Greenberg et al., 2000). In a case–control study, we selected 104 panic disorder researchparticipants (28 males and 76 females) from patients atthe Psychiatric Unit of Copenhagen University Hospital(Rigshospitalet). Diagnoses of panic anxiety disorderwere made according to the DSM-IV. All patients wereunrelated Scandinavians with a Caucasian genetic back-ground. The control group consisted of 108 healthy,unrelated individuals (30 men and 78 women). Compar-ison of the s and l allele frequencies between panicdisorder patients and controls revealed no differences.There were 86 s alleles (41%) and 122 l alleles (59%) inthe cases and 89 s alleles (41%) and 127 l alleles (59%) inthe controls. The genotype distribution revealed aslightly higher frequency of heterozygous panic disorderpatients than controls, but the difference was notsignificant. Stratification of the patient population intogender also failed to suggest any predominance of thes allele in either male or female panic disorder patients.We further examined whether the age-of-onset of panicdisorder was correlated to the genotype. To do so, wecalculated the mean age of the first episode of panicdisorder, but found no differences between homozygouss/s (27 years), homozygous l/l (28 years), or heterozygousl/s patients (27 years). The panic disorder groupcomprised patients with only panic disorder as well aspatients with comorbidity of phobia, either agoraphobia orsocial phobia. Patients with phobia had a trend towardsheterozygity. Allele frequencies revealed no differencesbetween either of the panic disorder subgroups and thecontrol group. Approximately half of the patients in thisstudy had a family history of either panic disorder orunipolar depression. This subgroup had a skeweddistribution of genotypes or alleles, but we failed todetect any significant differences between panic disorderpatients with or without a family history.

Variations in 5-HTTLPR: Relation to familiar risk of affective disorder, life events, neuroticism and cortisol

BACKGROUND Variations in the serotonin transporter gene (5-HTTLPR) and stressful life events are associated with affective disorders. AIM To investigate whether the distribution of the alleles of the 5-HTTLPR is associated with a genetic predisposition to affective disorder and whether these variations interact with life events in relation to depressive symptoms, neuroticism and salivary cortisol. METHOD In a high-risk population study, healthy monozygotic and dizygotic twins with (high-risk twins) and without (low-risk twins) a co-twin history of affective disorder were identified through nationwide registers. RESULTS When comparing the 81 individuals homozygote for the long allele with the 125 individuals hetero- and homozygote for the short allele no associations between the allele distribution and a genetic predisposition were found. The presence of the short allele of the 5-HTTLPR and the experience of SLE was associated with a higher neuroticism score, but not with depressive symptoms nor awakening or evening salivary cortisol. CONCLUSION A combination of variants in 5-HTTLPR and environmental stress seems to increase neuroticism in healthy individuals.

Combinations of SNPs related to signal transduction in bipolar disorder.

Any given single nucleotide polymorphism (SNP) in a genome may have little or no functional impact. A biologically significant effect may possibly emerge only when a number of key SNP-related genotypes occur together in a single organism. Thus, in analysis of many SNPs in association studies of complex diseases, it may be useful to look at combinations of genotypes. Genes related to signal transmission, e.g., ion channel genes, may be of interest in this respect in the context of bipolar disorder. In the present study, we analysed 803 SNPs in 55 genes related to aspects of signal transmission and calculated all combinations of three genotypes from the 3×803 SNP genotypes for 1355 controls and 607 patients with bipolar disorder. Four clusters of patient-specific combinations were identified. Permutation tests indicated that some of these combinations might be related to bipolar disorder. The WTCCC bipolar dataset were use for replication, 469 of the 803 SNP were present in the WTCCC dataset either directly (n = 132) or by imputation (n = 337) covering 51 of our selected genes. We found three clusters of patient-specific 3×SNP combinations in the WTCCC dataset. Different SNPs were involved in the clusters in the two datasets. The present analyses of the combinations of SNP genotypes support a role for both genetic heterogeneity and interactions in the genetic architecture of bipolar disorder.

Are variations in whole blood BDNF level associated with the BDNF Val66Met polymorphism in patients with first episode depression

Brain derived neurotrophic factor (BDNF) seems to play an important role in the pathophysiology of affective disorders. The current study investigated whether blood level BDNF is correlated with the severity of depressive symptoms and recent (six months prior to onset of depression) experience of stressful life events (SLE) in a cohort of patients with a first depressive episode. 262 patients with first episode depression (females 174, males 88, age range 18-70, mean age 41) participated and control sample of 84 participants was included (females 52, males 32, age range 22-70, mean age 42). Symptomatology was rated using Hamilton Rating Scale for Depression (HAMD-17) and Becks Depression Inventory (BDI 21). No differences in whole blood BDNF was seen in relation to the BDNF Val66Met polymorphism and no significant correlations between whole blood BDNF and HAMD-17 or BDI 21 scores were found. No significant associations between the experiences of SLE before onset of depression and BDNF level were observed. Finally, peripheral BDNF differentiated between patients and healthy control persons. In the current sample of first episode depressed patients, the Val66Met polymorphism was not associated with whole blood BDNF and whole blood BNDF level was not associated with the experience of recent SLE.

Connection between Genetic and Clinical Data in Bipolar Disorder

Complex diseases may be associated with combinations of changes in DNA, where the single change has little impact alone. In a previous study of patients with bipolar disorder and controls combinations of SNP genotypes were analyzed, and four large clusters of combinations were found to be significantly associated with bipolar disorder. It has now been found that these clusters may be connected to clinical data.

Combinations of Genetic Data Present in Bipolar Patients, but Absent in Control Persons

The main objective of the study was to find combinations of genetic variants significantly associated with bipolar disorder. In a previous study of bipolar disorder, combinations of three single nucleotide polymorphism (SNP) genotypes taken from 803 SNPs were analyzed, and four clusters of combinations were found to be significantly associated with bipolar disorder. In the present study, combinations of four SNP genotypes taken from the same 803 SNPs were analyzed, and one cluster of combinations was found to be significantly associated with bipolar disorder. Combinations from the new cluster and from the four previous clusters were identified in the genomes of 209 of the 607 patients in the study whereas none of the 1355 control participants had any of these combinations in their genome.

Combinations of genetic variants associated with bipolar disorder

The main objective of the study was to find genetic variants that in combination are significantly associated with bipolar disorder. In previous studies of bipolar disorder, combinations of three and four single nucleotide polymorphisms (SNP) genotypes taken from 803 SNPs were analyzed, and five clusters of combinations were found to be significantly associated with bipolar disorder. In the present study, combinations of ten SNP genotypes taken from the same 803 SNPs were analyzed, and one cluster of combinations was found to be significantly associated with bipolar disorder. Combinations from the new cluster and from the five previous clusters were identified in the genomes of 266 or 44% of the 607 patients in the study whereas none of the 1355 control participants had any of these combinations in their genome.The SNP genotypes in the smaller combinations were the normal homozygote, heterozygote or variant homozygote. In the combinations containing 10 SNP genotypes almost all the genotypes were the normal homozygote. Such a finding may indicate that accumulation in the genome of combinations containing few SNP genotypes may be a risk factor for bipolar disorder when those combinations contain relatively many rare SNP genotypes, whereas combinations need to contain many SNP genotypes to be a risk factor when most of the SNP genotypes are the normal homozygote.