Molecular Genetics of Brain Derived Neurotrophic Factor

许多研究表明，长期的严重抑郁障碍(MDD)与选择性地丧失海马体体积有关，这种丧失在抑郁症缓解后很长一段时间内持续存在。离子型谷氨酸受体亚型和细胞死亡途径很可能参与了这一过程。诱导内源性神经通路，如那些增加BDNF水平的通路，可以防止神经元丢失。此外，糖皮质激素，应激期间分泌的肾上腺类固醇，也可能在神经元丢失中发挥作用。IGR的激活，特别是NMDA亚型受体、神经营养因子的释放和合成的相互作用对维持神经元的活性至关重要。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地影响神经元的存活。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。BDNF(BDNF)和TrkB(NTRK2)基因作为易患成瘾和其他精神疾病的候选基因，包括焦虑和MDD，受到越来越多的关注。MDD与酒精中毒有显著的共病关系，尽管MDD对酒精中毒的作用还不是很清楚。 通过以上讨论，可以预期BDNF变异可能会影响行为。最近的几项研究着眼于功能性BDNF Val66Met变体与人类精神病理学之间的关系。结果是相互矛盾的。除了在研究设计、基因分型和数据分析方面的差异外，这种缺乏共识的一个可能性是，可能存在其他BDNF功能等位基因，并在精神病理学中发挥作用。 根据差异表达结果和多个BDNF启动子指导其转录的事实，我们采用变异发现的方法鉴定了BDNF启动子区域的两个序列变异和5？未翻译的外显子1和4。此外，在美国高加索人、美国印第安人和非洲裔美国人中进行了基因分型。采用终生DSM-III-R精神病学诊断标准，采用三维人格问卷(TPQ)测量焦虑气质(伤害回避[HA])和新奇追求(NS)。在BDNF启动子1中发现了一个新的SNP(NT-281)，它在体外与DNA结合减少，并降低了转基因大鼠海马神经元的基础报告基因活性。-281a等位基因在高加索人群中的频率为0.03，而在其他人群中几乎不存在。基于社区白种人样本的单等位基因关联研究表明，携带-281a等位基因(13个杂合子)的个体具有较低的TPQ HA(F=4.8，p&lt；0.05)，并且更不可能有精神疾病诊断(0.69vs0.47，？2=2.4，p=0.12)。相反，Met 66等位基因与HA升高有关(F=4.1，p=0.02)，并且在同时患有焦虑症和重度抑郁症的个体中最为丰富(p&lt；0.05)。在这个人群中，低活性的？281a等位基因可能对焦虑和精神疾病有保护作用，而Met 66可能是一个危险的等位基因。

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.