精神分裂症的候选基因研究
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摘要
背景：已有一些连锁分析的研究提示染色体22q和6p可能聚集着精神分裂症的易感基因。我们的前期研究也在这两个区域发现了高LOD分，尤其是在22q11-12发现了显著性的连锁(LOD分高达4.63)。位于染色体6p21的NOTCH4基因曾被报导与精神分裂症关联，但随后的研究并没有重复到他们之间的关联。对于染色体22q，有研究发现位于编码β-肾上腺素能受体酶2(beta-adrenergic receptor kinase 2，ADRBK2)的基因的内含子中的DNA标记D22S315与精神分裂症成显著性的连锁，我们的前期研究也在这一基因附近的DNA标记中产生了高LOD分。因此，本研究假设NOTCH4和ADRBK2基因为精神分裂症的易感基因而进行了研究。
方法：我们收集了16个由父母和患病子女组成的日本人精神分裂症核心家庭，以及107个中国人汉族精神分裂症核心家庭，即总共123名先证者(患病子女)和246名父母。101个中国人核心家庭成员完成了PANSS量表评定。对于NOTCH4基因，在所有样本中对位于基因上游的单核苷酸多态(single nucleotide polymorphisms，SNP)SNP1和外显子1中的微卫星片段(CTG)n分别通过测序和基因扫描进行了基因分型。对于ADRBK2基因，在48名先证者(16名日本人和32名中国人)中进行突变筛查，对ADRBK2的21个外显子的所有序列及外显子与内含子邻接区域的部分内含子进行了测序；同时对突变筛查中发现的错义突变及JSNP数据库中的有关SNP，对64个核心家庭(16个日本人核心家庭，48个中国人核心家庭)的成员进行了基因分型。
结果：对于NOTCH4基因，在先前研究报导的SNP1(Wei和Hemming 2000)的附近，我们发现了4个新的SNP(SNP_A—D)，并对所有样本进行了基因分型。传递不平衡检验(Transmission／disequilibrium Test，TDT)结果显示精神分裂症与6个多态之间不存在着显著性的关联。当单独分析样本量较大的中国人样本时，仍然不存在着关联。但当考虑到临床特征的异质性时，我们发现SNP_A可能与早发性精神分裂症关联，SNP1可能与有很多阴性症状的精神分裂症关联。对于ADRBK2基因，在外显子及外显子与内含子交接区域内共发现了15个新的
变异，其中在编码区发现了一个罕见的错义变异Kps208S叫和两个同义变异。
”错义变异Q5208hr仅发生干一个家庭，与精神分裂症不存在着显著性的关联，
耐另外8个SNP的TDT结果也没有显示与精神分裂症之间存在着显著性的
关联。
结论：当忽视D锹－时，＊0＊＊＊4似乎不与精神分裂症关联。但当釉到
I临床异质哪，NOTCH4可能与早发性精神分裂症或有很多阴腕状的精神分
裂症关联。在我们的研究人群中，ADAnKZ基因中存在着较低的核苦酸差异性，
与精神分裂症不存在着遗传性的关联。
Background: Several genome-wide linkage studies including our previous linkage study have suggested that chromosome 22ql2 and 6p may be harbor risk genes for schizophrenia. In the original candidate gene study, the NOTCH4 gene located in the 6p21.3, had been reported that there was an association with schizophrenia in a family-based association study in a British sample. However, all six subsequent replication studies failed to confirm the finding. On the other hand, with respect to 22q, significant linkage of intermediate phenotypes for schizophrenia in two independent studies was reported to markers within or near the beta-adrenergic receptor kinase 2 (ADRBK2) gene, which mediates homologus desensitization for a variety of neurotransmitters and hormones through phosphorylation of G protein-coupled receptors (GPCRs). We hypothesized that the ADRBK2 and NOTCH4 genes are susceptibility genes for schizophrenia.
Methods: One hundred twenty three parent-offspring schizophrenic trios (16 Japanese trios and 107 Chinese trios) were recruited. For NOTCH4 gene, the single nucleotide polymorphisms (SNP) -- SNP1, and (CTG)n microsatalite repeat reported by original study were genotyped in all subjects through direct sequencing and PCR by capillary electrophoresis, respectively. For ADRBK2 gene, systematically mutation screening was performed in all 21 exonic and flanking intronic regions through direct sequencing in 48 schizophrenia probands (including 16 Japanese and 32 Chinese probands) randomly selected from our subjects, and the detected variants and eight SNPs reported in the JSNP database were genotyped in 64 trios. Results: For NOTCH4 gene, in addition to the original study's
polymorphisms, we detected four new SNPs - SNPs_A, B, C and D, which all are around SNP1 of the original study. We genotyped all samples for SNPs_A-D, besides SNP1 and (CTG)n of the original study. No significant associations were found between NOTCH4 and schizophrenia for all six polymorphisms. This finding remained negative when the Chinese sample was analyzed separately. However, when we took the clinical heterogeneity into account, our results showed that SNP_A may be associated with early-onset schizophrenia, and SNP1 may be associated with schizophrenia characterized by many negative symptoms. On the other hand, for ADRBK2 gene, although 15 novel single nucleotide variants were found in exonic and flanking intronic regions, the frequency of variants were very low, and only one rare missense variant and two silent variants were found in coding region. The missense variant Cys208Ser was only found in one family among 123 trios, and did not show any evidence for association with schizophrenia; Moreover, no association was obtained between the other 10 SNPs (two variants detected by mutation screening and 8 SNPs from JSNP) and schizophrenia.
Conclusions: NOTCH4 is not a significant susceptibility gene for schizophrenia when clinical heterogeneity is ignored. However, NOTCH4 may associate with early-onset schizophrenia or schizophrenia with many negative symptoms, when clinical homogenous being taken into consideration. On the other hand, for ADRBK2 gene, our results suggest low nucleotide diversity in the ADRBK2 gene, and indicate that ADRJBK2 is unlikely to contribute strongly to schizophrenia susceptibility in this set of families.
方法：我们收集了16个由父母和患病子女组成的日本人精神分裂症核心家庭，以及107个中国人汉族精神分裂症核心家庭，即总共123名先证者(患病子女)和246名父母。101个中国人核心家庭成员完成了PANSS量表评定。对于NOTCH4基因，在所有样本中对位于基因上游的单核苷酸多态(single nucleotide polymorphisms，SNP)SNP1和外显子1中的微卫星片段(CTG)n分别通过测序和基因扫描进行了基因分型。对于ADRBK2基因，在48名先证者(16名日本人和32名中国人)中进行突变筛查，对ADRBK2的21个外显子的所有序列及外显子与内含子邻接区域的部分内含子进行了测序；同时对突变筛查中发现的错义突变及JSNP数据库中的有关SNP，对64个核心家庭(16个日本人核心家庭，48个中国人核心家庭)的成员进行了基因分型。
结果：对于NOTCH4基因，在先前研究报导的SNP1(Wei和Hemming 2000)的附近，我们发现了4个新的SNP(SNP_A—D)，并对所有样本进行了基因分型。传递不平衡检验(Transmission／disequilibrium Test，TDT)结果显示精神分裂症与6个多态之间不存在着显著性的关联。当单独分析样本量较大的中国人样本时，仍然不存在着关联。但当考虑到临床特征的异质性时，我们发现SNP_A可能与早发性精神分裂症关联，SNP1可能与有很多阴性症状的精神分裂症关联。对于ADRBK2基因，在外显子及外显子与内含子交接区域内共发现了15个新的
变异，其中在编码区发现了一个罕见的错义变异Kps208S叫和两个同义变异。
”错义变异Q5208hr仅发生干一个家庭，与精神分裂症不存在着显著性的关联，
耐另外8个SNP的TDT结果也没有显示与精神分裂症之间存在着显著性的
关联。
结论：当忽视D锹－时，＊0＊＊＊4似乎不与精神分裂症关联。但当釉到
I临床异质哪，NOTCH4可能与早发性精神分裂症或有很多阴腕状的精神分
裂症关联。在我们的研究人群中，ADAnKZ基因中存在着较低的核苦酸差异性，
与精神分裂症不存在着遗传性的关联。
Background: Several genome-wide linkage studies including our previous linkage study have suggested that chromosome 22ql2 and 6p may be harbor risk genes for schizophrenia. In the original candidate gene study, the NOTCH4 gene located in the 6p21.3, had been reported that there was an association with schizophrenia in a family-based association study in a British sample. However, all six subsequent replication studies failed to confirm the finding. On the other hand, with respect to 22q, significant linkage of intermediate phenotypes for schizophrenia in two independent studies was reported to markers within or near the beta-adrenergic receptor kinase 2 (ADRBK2) gene, which mediates homologus desensitization for a variety of neurotransmitters and hormones through phosphorylation of G protein-coupled receptors (GPCRs). We hypothesized that the ADRBK2 and NOTCH4 genes are susceptibility genes for schizophrenia.
Methods: One hundred twenty three parent-offspring schizophrenic trios (16 Japanese trios and 107 Chinese trios) were recruited. For NOTCH4 gene, the single nucleotide polymorphisms (SNP) -- SNP1, and (CTG)n microsatalite repeat reported by original study were genotyped in all subjects through direct sequencing and PCR by capillary electrophoresis, respectively. For ADRBK2 gene, systematically mutation screening was performed in all 21 exonic and flanking intronic regions through direct sequencing in 48 schizophrenia probands (including 16 Japanese and 32 Chinese probands) randomly selected from our subjects, and the detected variants and eight SNPs reported in the JSNP database were genotyped in 64 trios. Results: For NOTCH4 gene, in addition to the original study's
polymorphisms, we detected four new SNPs - SNPs_A, B, C and D, which all are around SNP1 of the original study. We genotyped all samples for SNPs_A-D, besides SNP1 and (CTG)n of the original study. No significant associations were found between NOTCH4 and schizophrenia for all six polymorphisms. This finding remained negative when the Chinese sample was analyzed separately. However, when we took the clinical heterogeneity into account, our results showed that SNP_A may be associated with early-onset schizophrenia, and SNP1 may be associated with schizophrenia characterized by many negative symptoms. On the other hand, for ADRBK2 gene, although 15 novel single nucleotide variants were found in exonic and flanking intronic regions, the frequency of variants were very low, and only one rare missense variant and two silent variants were found in coding region. The missense variant Cys208Ser was only found in one family among 123 trios, and did not show any evidence for association with schizophrenia; Moreover, no association was obtained between the other 10 SNPs (two variants detected by mutation screening and 8 SNPs from JSNP) and schizophrenia.
Conclusions: NOTCH4 is not a significant susceptibility gene for schizophrenia when clinical heterogeneity is ignored. However, NOTCH4 may associate with early-onset schizophrenia or schizophrenia with many negative symptoms, when clinical homogenous being taken into consideration. On the other hand, for ADRBK2 gene, our results suggest low nucleotide diversity in the ADRBK2 gene, and indicate that ADRJBK2 is unlikely to contribute strongly to schizophrenia susceptibility in this set of families.
引文
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