Instituto Gulbenkian de Ciência, Oeiras, Portugal.
Genes Brain Behav. 2010 Oct;9(7):841-8. doi: 10.1111/j.1601-183X.2010.00627.x. Epub 2010 Aug 19.
The brain-derived neurotrophic factor (BDNF), a neurotrophin fundamental for brain development and function, has previously been implicated in autism. In this study, the levels of BDNF in platelet-rich plasma were compared between autistic and control children, and the role of two genetic factors that might regulate this neurotrophin and contribute to autism etiology, BDNF and NTRK2, was examined. We found that BDNF levels in autistic children (n = 146) were significantly higher (t = 6.82; P < 0.0001) than in control children (n = 50) and were positively correlated with platelet serotonin distribution (r = 0.22; P = 0.004). Heritability of BDNF was estimated at 30% and therefore candidate genes BDNF and NTRK2 were tested for association with BDNF level distribution in this sample, and with autism in 469 trio families. Genetic association analysis provided no evidence for BDNF or NTRK2 as major determinants of the abnormally increased BDNF levels in autistic children. A significant association with autism was uncovered for six single nucleotide polymorphisms (SNPs) [0.004 (Z((1df)) = 2.85) < P < 0.039 (Z((1df)) = 2.06)] and multiple haplotypes [5 × 10(-4) (χ((3df)) = 17.77) < P < 0.042 (χ((9df)) = 17.450)] in the NTRK2 gene. These results do not withstand correction for multiple comparisons, however, reflect a trend toward association that supports a role of NTRK2 as a susceptibility factor for the disorder. Genetic variation in the BDNF gene had no impact on autism risk. By substantiating the previously observed increase in BDNF levels in autistic children in a larger patient set, and suggesting a genetic association between NTRK2 and autism, this study integrates evidence from multiple levels supporting the hypothesis that alterations in BDNF/tyrosine kinase B (TrkB) signaling contribute to an increased vulnerability to autism.
脑源性神经营养因子（BDNF）是一种对大脑发育和功能至关重要的神经营养因子，先前已被牵连到自闭症中。在这项研究中，我们比较了自闭症儿童和对照组儿童富含血小板的血浆中的 BDNF 水平，并研究了两个可能调节这种神经营养因子并导致自闭症病因的遗传因素，即 BDNF 和 NTRK2。我们发现，自闭症儿童（n = 146）的 BDNF 水平明显高于对照组儿童（n = 50）（t = 6.82；P < 0.0001），且与血小板 5-羟色胺分布呈正相关（r = 0.22；P = 0.004）。BDNF 的遗传力估计为 30%，因此在该样本中测试了候选基因 BDNF 和 NTRK2 与 BDNF 水平分布的关联，以及与 469 个三亲家庭的自闭症的关联。遗传关联分析没有提供证据表明 BDNF 或 NTRK2 是自闭症儿童中 BDNF 水平异常升高的主要决定因素。在 NTRK2 基因中发现了六个单核苷酸多态性（SNP）[0.004（Z((1df)) = 2.85）< P < 0.039（Z((1df)) = 2.06）]和多个单倍型[5 × 10(-4)（χ((3df)) = 17.77）< P < 0.042（χ((9df)) = 17.450）]与自闭症显著相关。然而，这些结果在经过多次比较的校正后并不成立，反映了关联的趋势，支持 NTRK2 作为该疾病易感性因素的作用。BDNF 基因的遗传变异对自闭症风险没有影响。通过在更大的患者群体中证实自闭症儿童中先前观察到的 BDNF 水平升高，并表明 NTRK2 与自闭症之间存在遗传关联，这项研究整合了来自多个层面的证据，支持 BDNF/酪氨酸激酶 B（TrkB）信号改变导致自闭症易感性增加的假说。
