Molecular Genetics of Brain Derived Neurotrophic Factor

许多研究表明，长期的重度抑郁症（MDD）与海马体积的选择性损失有关，这种损失在抑郁症消退后很长一段时间内仍然存在。这一过程很可能与嗜离子性谷氨酸受体亚型和凋亡细胞死亡途径有关。内源性神经元通路的诱导，如BDNF水平的增加，可以防止神经元的损失。此外，应激时分泌的肾上腺类固醇糖皮质激素也可能在神经元丢失中发挥作用。IGR活化的相互作用，特别是NMDA亚型受体，神经营养因子的释放和合成对维持神经元活力至关重要。IGR基因、神经营养因子基因和应激途径的遗传变异可能深刻影响神经元的生存能力。BDNF与受体酪氨酸激酶（TrkB）相互作用，允许神经元存活和突触加强。人们对BDNF （BDNF）和TrkB （NTRK2）基因越来越感兴趣，因为它们是成瘾和其他精神疾病（包括焦虑和重度抑郁症）易感性的候选基因。重度抑郁症与酒精中毒有显著的共病性，尽管重度抑郁症对酒精中毒的影响尚不清楚。

A number of studies have indicated that prolonged, major depression disorder (MDD) is associated with a selective loss of hippocampal volume that persists long after the depression has resolved. Ionotropic glutamate receptor subtypes and apoptotic cell death pathways are very likely to be involved in this process. The induction of endogenous neuronal pathways, such as those increasing BDNF levels, can prevent neuronal loss. In addition, glucocorticoids, the adrenal steroids secreted during stress, may also play a contributing role in neuron loss. The interplay of IGR activation, particularly receptors of the NMDA subtype, neurotrophin release and synthesis are critical to maintaining neuronal viability. Genetic variation in IGR genes, neurotrophin genes, and stress pathways are likely to profoundly influence neuronal viability. BDNF interacts with a receptor tyrosine kinase (TrkB), allowing for neuronal survival and synaptic strengthening. There is growing interest in the BDNF (BDNF) and the TrkB (NTRK2) genes as candidates for vulnerability to addictions and other psychiatric conditions, including anxiety and MDD. MDD shares significant comorbidity with alcoholism, although the contribution of MDD to alcoholism is not well understood. From the foregoing discussion it could be expected that BDNF variation might influence behavior. Several recent studies have looked at the relationship between the functional BDNF Val66Met variant and psychopathology in humans. The results have been conflicting. Apart from differences in study design, genotyping, and data analysis, one possibility for this lack of consensus is that other BDNF functional alleles may be present and have a role in psychopathology. Based on differential expression results and on the fact that multiple BDNF promoters direct its transcription, we used variant discovery approaches to identify two sequence variants in BDNF promoter regions and two variants in 5? untranslated exons 1 and 4. In addition, genotyping was performed in U.S. Caucasian, American Indian, and African American populations. Lifetime DSM-III-R psychiatric diagnoses were assigned and the Tridimensional Personality Questionnaire (TPQ) administered to measure anxious temperament (harm avoidance [HA]) and novelty seeking (NS). A novel SNP was discovered (nt -281) in BDNF promoter 1 with decreased DNA binding in vitro and decreased basal reporter gene activity in transfected rat hippocampal neurons. The frequency of the -281A allele was 0.03 in a Caucasian sample but was virtually absent in other populations. Single allele-based association studies in a community-based Caucasian sample showed that individuals with the -281A allele (13 heterozygotes) had lower TPQ HA (F = 4.8, p < 0.05) and were less likely to have a psychiatric diagnosis (0.69 v 0.47, ?2 = 2.4, p = 0.12). In contrast, the Met 66 allele was associated with increased HA (F = 4.1, p = 0.02) and was most abundant in individuals with both anxiety disorders and major depression (p < 0.05). In this population, the low activity ?281A allele may be protective against anxiety and psychiatric morbidity whereas Met 66 may be a risk allele.