The BDNF gene confers risk in an age-dependent manner on the brain structures and cognitive functions that are consistent with the neural circuitry vulnerable in the earliest stages of AD. Our novel findings provide convergent evidence in vivo for a BDNF genetic mechanism of susceptibility in an intermediate phenotype related to AD.

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

Brain-derived neurotrophic factor (BDNF) is a nerve growth factor that has antidepressant-like effects in animals. BDNF gene polymorphisms have been associated with bipolar disorder. We tested two genetic polymorphisms of BDNF for their association with childhood-onset mood disorders (COMD) within the context of a case-control design. Two BDNF polymorphisms, a dinucleotide repeat (GT)(n), and a single nucleotide polymorphism (SNP) in the coding region, val66met, were genotyped in 99 adults with a history of COMD and matched psychiatrically healthy controls. A genomic control (GC) method was used to evaluate population substructure. Alleles at (GT)(n) were highly associated with COMD in this sample (chi(2) = 17.8; d.f. = 5; P = 0.0032). The odds of carrying the 168 bp allele were 3.94 times greater for cases than controls (CI = 1.72-9.04). Alleles of val66met were not significantly associated with COMD. GC analysis suggested population substructure was not a confounder of association. Analysis of haplotypes, in which (GT)(n) was treated as a binary variable (long vs. short alleles), provided significant evidence that the haplotype val/short contributes to liability to COMD. The BDNF (GT)(n) marker and the val/short haplotype are associated with COMD in this sample, in accordance with the previously described neurotrophic hypothesis of depression and some previous studies of association for bipolar disorder and neuroticism.