Evidence that a single nucleotide polymorphism in the promoter of the G protein receptor kinase 3 gene is associated with bipolar disorder
Evidence that a single nucleotide polymorphism in the promoter of the G protein receptor kinase 3 gene is associated with bipolar disorder
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DOI：
10.1038/sj.mp.4001268
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发表时间：
2003-01-01
影响因子：
11
通讯作者：
Kelsoe, JR
中科院分区：
文献类型：
--
作者：
Barrett, TB;Hauger, RL;Kelsoe, JR
在全基因组连锁调查中，我们之前的证据表明染色体 22q12 区域包含双相情感障碍 (BPD) 的易感位点。两个独立的家族组产生的 lod 分数表明该区域中 G 蛋白受体激酶 3 (GRK3) 基因附近的标记存在连锁。 GRK3 是 BPD 的绝佳候选风险基因，因为 GRK3 在大脑中广泛表达，并且 GRK 在 G 蛋白偶联受体信号转导的同源脱敏中发挥关键作用。我们之前还使用基于微阵列的表达谱显示了躁狂动物模型中安非他明诱导的 GRK3 表达。为了鉴定 GRK3 中可能的功能突变，我们对 14-22 名 BPD 患者的推定启动子区域、所有 21 个外显子以及每个外显子侧翼的内含子序列进行了测序。我们在 50-UTR/启动子区域发现了 6 个序列变异，但没有编码或明显的剪接变异。对一组 153 个家族的传递不平衡分析表明，其中两个 5'-UTR/启动子变异与北欧高加索血统家族中的 BPD 相关。随后在 237 个家庭的独立样本中获得了与这两种变体之一 (P-5) 相关的支持趋势。在合并样本中，P-5 变体在双相情感障碍受试者中的等位基因频率估计为 3%，传播与非传播之比为 26: 7.7（chi(2) = 9.6，单侧 P 值 = 0.0019）。总而言之，这些数据支持这样的假设：GRK3 表达失调会改变信号脱敏，从而导致 BPD 的发生。
In a genome-wide linkage survey, we have previously shown evidence suggesting that the chromosome 22q12 region contains a susceptibility locus for bipolar disorder (BPD). Two independent family sets yielded lod scores suggestive of linkage at markers in this region near the gene G protein receptor kinase 3 (GRK3). GRK3 is an excellent candidate risk gene for BPD since GRK3 is expressed widely in the brain, and since GRKs play key roles in the homologous desensitization of G protein-coupled receptor signaling. We have also previously shown GRK3 expression to be induced by amphetamine in an animal model of mania using microarray-based expression profiling. To identify possible functional mutations in GRK3, we sequenced the putative promoter region, all 21 exons, and intronic sequence flanking each exon, in 14-22 individuals with BPD. We found six sequence variants in the 50-UTR/promoter region, but no coding or obvious splice variants. Transmission disequilibrium analyses of one set of 153 families indicated that two of the 5'-UTR/promoter variants are associated with BPD in families of northern European Caucasian ancestry. A supportive trend towards association to one of these two variants (P-5) was then subsequently obtained in an independent sample of 237 families. In the combined sample, the P-5 variant had an estimated allele frequency of 3% in bipolar subjects, and displayed a transmission to non-transmission ratio of 26 : 7.7 (chi(2) = 9.6, one-sided P value = 0.0019). Altogether, these data support the hypothesis that a dysregulation in GRK3 expression alters signaling desensitization, and thereby predisposes to the development of BPD.