Brain-Derived Neurotrophic Factor Val/Met Polymorphism and Bipolar Disorder

Background/Aims: The substitution of valine by methionine in the brain-derived neurotrophic factor (BDNF Val/Met) gene alters the intracellular trafficking and regulated secretion of BDNF. This study tested whether the BDNF Val/Met polymorphism is associated with bipolar disorder in Korean subjects, and whether clinical features vary according to genotype. Methods: The allelic and genotypic distributions of BDNF Val/Met were determined in a population of 169 bipolar patients and 251 normal controls. Between-genotype comparisons of clinical features were performed without a priori knowledge of the genotype of individual patients. Results: Allelic distributions did not differ significantly between bipolar patients and controls ( 2 = 0.400, p = 0.821). However, the rate of suicide attempts among the Val/Val (11.3%), Val/Met (28.8%) and Met/Met (38.9%) genotype groups were significantly different ( 2 = 9.879, p = 0.007). Relative to patients with the Val/Val genotype, those with the Met/Met genotype had a 4.9-fold higher risk of suicide attempts (95% CI, 1.7–14.7). Conclusions: These findings suggest that BDNF Val/Met is related to the suicidal behavior of bipolar patients, and may have clinical relevance as a biological indicator of bipolar patients at risk of suicide. Copyright © 2008 S. Karger AG, Basel Received: October 9, 2007 Accepted after revision: July 29, 2008 Published online: October 9, 2008 Yeon Ho Joo, MD, PhD Department of Psychiatry, Asan Medical Center University of Ulsan College of Medicine Pungnap-2dong, Songpa-gu, Seoul, 138-736 (Korea) Tel. +82 2 3010 3412, Fax +82 2 485 8381, E-Mail [email protected] © 2008 S. Karger AG, Basel 0302–282X/08/0582–0097$24.50/0 Accessible online at: www.karger.com/nps D ow nl oa de d by : 54 .7 0. 40 .1 1 11 /6 /2 01 7 7: 13 :1 1 P M Kim/Kim/Hong/Kim/Lee/Joo Neuropsychobiology 2008;58:97–103 98 human subjects, including poorer episodic memory [15] , reduced hippocampal volume [17, 18] and reduced gray matter volume in the dorsolateral prefrontal cortex [18] . Although the Val/Met polymorphism has functional effects, the biological relevance of this polymorphism to bipolar disorder remains unclear. Two family-based studies found that BDNF Val/Met has a significant association with bipolar disorder, with the Val allele showing increased susceptibility [11, 12] . Additional attempts to replicate these findings, however, have yielded inconsistent results [19] . In particular, a negative association between BDNF Val/Met and bipolar disorder was observed in Japanese and Han Chinese subjects [20–22] , whereas a positive association was observed in predominantly Caucasian populations [11, 12, 23] . Moreover, the allele frequencies of BDNF Val/Met have been found to differ significantly between individuals of European and Asian descent [24] , suggesting that the association of BDNF Val/Met with bipolar disorder should be assessed separately in different ethnic populations. To our knowledge, there have been no studies to date on the association of BDNF Val/Met with bipolar disorder in Koreans. Instead of exerting a global influence in bipolar disorder, BDNF Val/Met may have a role in specific subgroups of bipolar patients or those with particular psychiatric symptom(s). For example, BDNF Val/Met was shown to be associated with childhood-onset affective disorder [25, 26] and rapid cycling [27, 28] . Moreover, this polymorphism may contribute to the development of particular clinical subphenotypes rather than bipolar disorder per se. For example, bipolar patients with the Met allele performed more poorly on the Wisconsin Card Sorting Test than bipolar patients homozygous for the Val allele [29–31] , indicating that this polymorphism may be associated with different clinical variables commonly present in bipolar disorder. Thus, it is of interest to determine the association of BDNF Val/Met with clinical features that are frequently present in bipolar patients. This study was designed to test whether the BDNF Val/Met polymorphism is associated with bipolar disorder in Korean subjects, and whether clinical features vary according to genotype.