Alonso Pino, Gratacòs Mónica, Menchón José M, Saiz-Ruiz Jerónimo, Segalàs Cinto, Baca-García Enrique, Labad Javier, Fernández-Piqueras José, Real Eva, Vaquero Concepción, Pérez Mercedes, Dolengevich Helen, González Juan R, Bayés Mónica, de Cid Rafael, Vallejo Julio, Estivill Xavier
OCD Clinical and Research Unit, Psychiatry Department, Hospital Universitari de Bellvitge, Barcelona, Spain.
Biol Psychiatry. 2008 Mar 15;63(6):619-28. doi: 10.1016/j.biopsych.2007.06.020. Epub 2007 Sep 19.
Family, twin and molecular studies provide increasing evidence for the importance of genetic factors in obsessive-compulsive disorder (OCD). Recent work suggests that brain-derived neurotrophic factor (BDNF) may be involved in OCD pathophysiology. We used a linkage disequilibrium (LD)-mapping approach to investigate the role that BDNF and its specific receptor neurotrophic tyrosine kinase receptor type 2 (NTRK2) may play in increasing susceptibility to OCD.
Eight tag single nucleotide polymorphisms (tagSNPs) covering the BDNF gene region and 46 tagSNPs in the NTRK2 region were genotyped in 215 OCD patients and 342 control subjects. Single nucleotide polymorphism association and haplotype analysis were performed. The possible relationship between genetic factors and clinical characteristics including age of OCD onset, tic disorders, clinical dimensions, and family history of OCD were investigated.
Haplotype analysis revealed a significant association between OCD and a five-marker protective haplotype located toward the 5' of the BDNF gene (odds ratio [OR] = .80; 95% confidence interval [CI] = .69-.92; permutation p value = .006) containing the functional valine (Val)66-to-methionine (Met) variant. A significant association between a NTRK2 intronic SNP (rs2378672) and OCD was identified (p < .0001) in female patients under an additive model. A protective haplotype located in intron 19 of NTRK2 was also associated with OCD (OR = .76; 95% CI = .66-.87; permutation p value = .001).
These findings support a role for the BDNF/NTRK2 signaling pathway in genetic susceptibility to OCD.
家庭、双胞胎和分子研究越来越多地证明了遗传因素在强迫症（OCD）中的重要性。最近的研究表明，脑源性神经营养因子（BDNF）可能参与了强迫症的病理生理过程。我们采用连锁不平衡（LD）定位方法来研究BDNF及其特异性受体神经营养性酪氨酸激酶受体2型（NTRK2）在增加强迫症易感性中可能发挥的作用。
对215例强迫症患者和342例对照受试者进行基因分型，检测覆盖BDNF基因区域的8个标签单核苷酸多态性（tagSNP）和NTRK2区域的46个tagSNP。进行单核苷酸多态性关联分析和单倍型分析。研究了遗传因素与包括强迫症发病年龄、抽动障碍、临床维度和强迫症家族史等临床特征之间的可能关系。
单倍型分析显示，强迫症与位于BDNF基因5'端的一个五标记保护性单倍型之间存在显著关联（优势比[OR]=0.80；95%置信区间[CI]=0.69 - 0.92；置换p值=0.006），该单倍型包含功能性缬氨酸（Val）66 -蛋氨酸（Met）变体。在加性模型下，女性患者中一个NTRK2内含子单核苷酸多态性（rs2378672）与强迫症之间存在显著关联（p < 0.0001）。位于NTRK2第19内含子的一个保护性单倍型也与强迫症相关（OR = 0.76；95% CI = 0.66 - 0.87；置换p值=0.001）。
这些发现支持BDNF/NTRK2信号通路在强迫症遗传易感性中的作用。
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