1. ¹Centre for Addiction and Mental Health, University of Toronto, Toronto, ON, Canada
2. ²Department of Psychiatry, Cell and Molecular Division, Toronto Western Research Institute, University Health Network, Toronto, ON, Canada
3. ³Brain & Behaviour Programme, The Hospital for Sick Children, Toronto, ON, Canada
4. ⁴Western Psychiatric Institute and Clinic, University of Pittsburgh Medical Center, Pittsburgh, PA, USA
5. ⁵Department for Child and Adolescent Psychiatry, Szeged University, Szeged, Hungary
6. ⁶Vadaskert Hospital, Budapest, Hungary
7. ⁷Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

Correspondence: Dr J Strauss, Neurogenetics Section, Centre for Addiction and Mental Health, 250 College St, Toronto, ON, Canada M6S 3R4. E-mail: john_strauss@camh.net

⁸Members listed in acknowledgements.

Received 25 February 2005; Accepted 21 March 2005; Published online 3 May 2005.

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. BDNF markers included the (GT)_n microsatellite, Val⁶⁶Met and four other single-nucleotide polymorphisms (SNPs) distributed across the BDNF gene. Family-based association and evolutionary haplotype analysis methods were used. Analysis of linkage disequilibrium (LD) revealed substantial LD among all six polymorphisms. Analyses of the Val⁶⁶Met polymorphism demonstrated significant overtransmission of the val allele (²=7.12, d.f.=1, P=0.0076). Consistent with the pattern of LD, all other SNPs showed significant biased transmission. The (GT)_n microsatellite alleles also indicated a trend towards biased transmission (170 bp: Z=2.095, P=0.036). Significant haplotypes involved Val⁶⁶Met and BDNF2 (P=0.0029). In this Hungarian sample, we found all five BDNF SNPs tested and a haplotype containing the BDNF Val⁶⁶Met Val allele to be associated with COMD. These results provide evidence that BDNF variants affect liability to juvenile-onset mood disorders, supported by data from two independent samples.