Laboratorio de Neurociencia, Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil.
J Psychiatr Res. 2010 Aug;44(11):700-6. doi: 10.1016/j.jpsychires.2010.01.002. Epub 2010 Jan 29.
GDNF (glial-cell-line derived neurotrophic factor) is a potent neurotrophic factor for dopaminergic neurons. Neuropsychiatric diseases and their treatments are associated with alterations in the levels of both GDNF and its receptor family (GDNF family receptor alpha or GFRA). GFRA1, GFRA2 and GFRA3 are located in chromosomal regions with suggestive linkage to schizophrenia. In this study we analyzed polymorphisms located in all four known GFRA genes and examined association with schizophrenia and clozapine response. We examined SNPs across the genes GFRA1-4 in 219 matched case-control subjects, 85 small nuclear families and 140 schizophrenia patients taking clozapine for 6months. We observed that GFRA3 rs11242417 and GFRA1 rs11197557 variants were significantly associated with schizophrenia after combining results from both schizophrenia samples. Furthermore, we found an overtransmission of the G-C GFRA1 rs7920934-rs730357 haplotype to subjects with schizophrenia and association of A-T-G-G GFRA3 rs10036665-rs10952-rs11242417-rs7726580 with schizophrenia in the case-control sample. On the other hand, GFRA2 variants were not associated with schizophrenia diagnosis but subjects carrying T-G-G rs1128397-rs13250096-rs4567028 haplotype were more likely to respond to clozapine treatment. The statistical significance of results survived permutation testing but not Bonferroni correction. We also found nominally-significant evidence for interactions between GFRA1, 2 and 3 associated with schizophrenia and clozapine response, consistent with the locations of these three genes within linkage regions for schizophrenia.
GDNF（胶质细胞源性神经营养因子）是多巴胺能神经元的一种有效神经营养因子。神经精神疾病及其治疗与 GDNF 及其受体家族（GDNF 家族受体 alpha 或 GFRA）的水平变化有关。GFRA1、GFRA2 和 GFRA3 位于与精神分裂症有暗示性连锁的染色体区域。在这项研究中，我们分析了所有四个已知 GFRA 基因中的多态性，并研究了它们与精神分裂症和氯氮平反应的关系。我们在 219 对匹配的病例对照受试者、85 个小核家族和 140 名服用氯氮平 6 个月的精神分裂症患者中检查了 GFRA1-4 基因中的 SNPs。我们观察到，在结合两个精神分裂症样本的结果后，GFRA3 rs11242417 和 GFRA1 rs11197557 变体与精神分裂症显著相关。此外，我们发现 G-C GFRA1 rs7920934-rs730357 单倍型向精神分裂症患者的过度传递以及 A-T-G-G GFRA3 rs10036665-rs10952-rs11242417-rs7726580 与病例对照样本中精神分裂症的关联。另一方面，GFRA2 变体与精神分裂症诊断无关，但携带 T-G-G rs1128397-rs13250096-rs4567028 单倍型的受试者更有可能对氯氮平治疗有反应。结果在置换检验中具有统计学意义，但未通过 Bonferroni 校正。我们还发现，GFRA1、2 和 3 与精神分裂症和氯氮平反应相关的相互作用具有名义上的显著性证据，这与这三个基因在精神分裂症连锁区域内的位置一致。
