We report here the association of the methionine (Met) substitution for valine (Val) at codon 66 (Val66Met) of the BDNF
gene (rs6265) with major depression in Mexican-Americans. This same SNP is associated with alterations in brain anatomy and memory, and recently Chen et al.
] showed that a variant BDNF mouse (BDNFMet/Met
) reproduced the phenotypic hallmarks of humans with this variant allele. They showed that BDNFMet
was expressed in brain at normal levels, but its secretion from neurons was defective. Interestingly, when placed in stressful settings, BDNFMet/Met
mice exhibited increased anxiety-related behaviors that were not normalized by antidepressant treatment, which suggests that this may be a required pathway for antidepressant response.
Hong and colleagues [14
] were the first to suggest that associations of polymorphisms in the BDNF
gene and mood disorders may be dependent on ethnicity. They relied on the fact that the positive association between BDNF
gene rs6265 polymorphism and bipolar disorder had only been demonstrated for a Caucasian population but not for a Japanese or Chinese sample. Discrepant results on the association of the rs6265 polymorphism in different psychiatric disorders may reflect this fact. In major depression alone, results have been published supporting as well as discarding the association of rs6265 with the disorder [13
]. This work offers a new type of sample on which to test whether this particular SNP has an impact on major depressive disorder.
Our recruitment was specific for ethnic background, an important fact that differs our approach from others that typically recruit individuals from the same nationality and geographical area, but do not have ethnicity as the characteristic on which their recruitment strategy is built upon. To the best of our knowledge, this is the first report of association of a BDNF gene polymorphism and major depressive disorder in Mexican-Americans.
An important feature of this work is the uniformity of assessments. To fulfill the large sample sizes required by genetic research rapid diagnoses are often conducted at multiple sites by various teams, resulting in inconsistencies in phenotype characterization and reduced reproducibility of findings. A key feature of this study is that this sample was all studied in Spanish by a small group of highly trained and experienced research personnel.
Our findings suggest that in these ethnic groups, patients with major depression have an increased probability of carrying the G/G genotype. This finding is in contrast to that of Hwang et al.
] in a population of Taiwanese elders that had carriers of the A/A form as having an increased risk for depression. When comparing the two studies it is important to remember that the A/A genotype is extremely rare in non-Asiatic populations. Our sample had only two individuals with this genotype, precluding us from evaluating its effect on major depressive disorder. In another study involving a large sample of participants from the European Prospective Investigation into Cancer and Nutrition in Norfolk (EPIC) study, no association was found between the rs6265 polymorphism and diagnoses of depression by self-assessed instruments [19
]; however, those types of assessment do not have diagnostic reliability, and they do not characterize the phenotype of major depression. In a study similar in design to ours, Tsai and colleagues [18
] reported a lack of association between depression and the rs6265 polymorphism [13
]. In a two-site European study assessing three polymorphisms in the BDNF
gene, including rs6265, Schumacher and colleagues [12
] did not find them individually associated with depression. Replication of these negative findings was obtained when the sample of one of the sites was analyzed separately. However, when performing a haplotype analysis considering these polymorphisms a positive association was identified with major depressive disorder but not with the other psychiatric disorders studied.