Brain-derived neurotrophic factor variants are associated with childhood-onset mood disorder: confirmation in a Hungarian sample

Abstract

Brain-derived neurotrophic factor (BDNF) is a nerve growth factor that has been implicated in the neurobiology of depression. Our group has previously reported an association between a BDNF variant and childhood-onset mood disorder (COMD) in an adult sample from Pittsburgh. We hypothesize that variants at the BDNF locus are associated with COMD. Six BDNF polymorphisms were genotyped in 258 trios having juvenile probands with childhood-onset DSM-IV major depressive or dysthymic disorder. Keywords: neurotrophic factors; mood disorder; childhood-onset; genetic association; haplotype Mood disorders rank fourth among the most significant global public health problems. 1 The prevalence of the juvenile-onset subtype of depressive disorder increases dramatically across the years of childhood and adolescence, with an estimated lifetime prevalence close to 20% by late adolescence. 2 Juvenile-onset mood disorders are associated with serious morbidity, including recurrence, impaired interpersonal functioning, and increased risks of bipolar disorder and suicide. 2,3 The influence of hereditary factors on susceptibility to major depression has been documented based on twin and adoption studies. 4 Twin studies in youth have identified significant heritability for depressive symptoms. 5,6 It has also been proposed that genetic aspects of liability to mood disorder may be more readily identified in families of childhood-and adolescentonset probands. 7 Accordingly, first-degree relatives of childhood-onset mood disorder probands have higher rates of affective disorder than do first-degree relatives of adult-onset mood disorder probands. 8 Evidence from both preclinical and clinical studies implicates brain-derived neurotrophic factor (BDNF) in mood disorders. Altered BDNF expression in stress-related depression via cellular signalling has been described in animal models. Repeated antidepressant administration, including electroconvulsive seizures, is associated with increased hippocampal BDNF expression, neuronal plasticity and neurogenesis. 9-11 Human neuroimaging 12,13 post mortem 14 and clinical [15][16][17] investigations indirectly support the hypothesis that neurotrophic factors play a key role in depression. As well, human linkage studies in

Interaction between BDNF and Serotonin: Role in Mood Disorders

“…Moreover, the BDNF gene as well as the Val66Met polymorphism have been associated with increased risk for a number of neuropsychiatric disorders (Neves-Pereira et al, 2002;Sklar et al, 2002;Schumacher et al, 2005;Strauss et al, 2005;Okada et al, 2006).…”

“…In a recent study, Kaufman et al found that children carrying the met allele of the BDNF gene val66met polymorphism and two short alleles (s/s) of 5-HTTLPR had the highest depression scores, but that this vulnerability was only evident in children with maltreatment history (Kaufman et al, 2006). This result is somewhat surprising, because most reports studying the val66met polymorphism have suggested that the met allele is protective for anxiety (Lang et al, 2005;Hunnerkopf et al, 2007) depression (Schumacher et al, 2005;Strauss et al, 2005;Frodl et al, 2007), but see Jiang et al (2005), and bipolar disorder (Neves-Pereira et al, 2002;Sklar et al, 2002). Indeed, in a separate study, the prevalence of depression due to multiple life events was found to be dramatically increased in s/s elders with one met allele (Kim et al, 2007).…”

Molecular studies of major depressive disorder: the epigenetic perspective

“…The short allele is generally associated with reduced transporter activity and lower SLC6A4 expression 19 -precisely the functional effect of the SSRIs used to treat depression -although a recent study investigating allelic expression in the serotonin transporter gene found no correlation between expression levels and the promoter polymorphism. 20 Other genes that have been putatively associated with MDD include those encoding tryptophan hydroxylase, 21 brain-derived neurotrophic factor, 22,23 catechol-O-methyl transferase, 24 phospholipase A2, 25 the glucocorticoid receptor 26 and the serotonin receptor 1A, 27 although these findings still await convincing replication in other samples (see Levinson 28 a recent review).…”

Meta-analysis of the BDNF Val66Met polymorphism in major depressive disorder: effects of gender and ethnicity

“…Excluded: no MDD phenotype, 8,14,67,68,[85][86][87][88][89][90][91][92][93][94][95][96][97] no case-control design, 22,31,[98][99][100][101][102][103] no adults 104,105 and no Hardy-Weinberg equilibrium (HWE). 106 Included: Caucasian studies, 11,[33][34][35][36][37][38][39][40] Asian studies 19,21,[41][42][43] and gender studies.…”

“…29,30 Also, a family-based study showed the Val allele to be associated with childhood-onset mood disorders. 31 Other studies did not observe any association of the Val66Met polymorphism with MDD 11,[32][33][34] (see also Table 1). …”