IGF2BP2、SLC30A8基因多态性与精神分裂症发病的遗传学关联研究
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摘要
目的：精神分裂症是一组病因未明的精神疾病,具有思维、情感、行为等多方面的障碍,以精神活动和环境不协调为特征,属于多基因遗传性疾病。由于精神分裂症给社会和家庭造成长期沉重的负担,所以确定精神分裂症的病因并在基因水平上预防和治疗疾病是迫切需要解决的问题。2型糖尿病是当今世界威胁人类健康的重要疾病之一,也是许多疾病的重要危险因素,其发病机制至今不明。目前认为它是一种由遗传因素和环境因素共同作用所致的复杂性疾病。近十年来,许多学者都致力于T2DM易感基因的研究但进展缓慢。最近以欧洲白种人为主要研究对象的全基因组范围关联研究(genome-wide association study, GWAS)报道了一系列基因包括TCF7L2, SLC30A8, HHEX, CDKAL1, CDKN2A/B, IGF2BP2, FTO, PPARG, KCNJ11, EXT2和LOC387761的多态性变异可以显著增加T2DM的发病风险,给T2DM易感基因的研究带来了突破性的进展。但上述基因的多态性变异在其它种群中的作用还不清楚。本研究旨在阐明IGF2BP2基因和SLC30A8基因多态性与中国北方汉族人群精神分裂症和糖尿病发病的关系。
方法：收集790例中国北方汉族精神分裂症患者和1083例健康人对照组全血样品,从中提取基因组DNA,采用聚合酶链式反应-限制性片段长度多态性(PCR-RFLP)的方法,检测IGF2BP2基因rs4402960位和SLC30A8基因rsl3266634位点基因型。应用拟合优度χ2检验分析基因型频数分布是否符合Hardy-Weinberg平衡定律,应用χ2检验和数量性状分析分别进行等位基因、基因型以及各种临床表型的关联性分析。
结果：SLC30A8基因rsl3266634位点的基因型频数分布在精神分裂症病例组和对照组均符合Hardy-Weinberg平衡定律(P>0.05)。等位基因关联分析表明,C和T等位基因在病例组和对照组中的频数分布比较差异无显著性(P>0.05)；基因型关联分析表明,C/C、C/T和糖尿病T/T 3种基因型在病例组和对照组的频数分布比较差异无显著性(P>0.05)；等位基因、基因型频数分布与精神分裂症各种临床表型均无关联(P>0.05)。
IGF2BP2基因rs4402960位点的基因型频数分布在精神分裂症病例组和对照组均符合Hardy-Weinberg平衡定律(P>0.05)。等位基因关联分析表明,T和G等位基因在病例组和对照组中的频数分布比较,二者差异显著(χ2=7.056,P=0.008)；基因型关联分析表明,T/T、T/G和G/G 3种基因型在病例组和对照组的频数分布比较,二者也差异显著(χ2=7.316,P=0.026),提示rs4402960位点与精神分裂症发病相关联；等位基因和精神分裂症临床表型的关联性分析在精神分裂症病例组中,rs4402960位点的T和G等位基因频数分布分别与精神分裂症患者临床表型的各种阳性症状进行4格表χ2检验。结果发现,rs4402960位点等位基因只与关系妄想相关联(χ2=4.145,P=0.042),而与真性听幻觉、影响妄想、自责自罪妄想、虚无妄想、读心症、被害妄想、嫉妒妄想、夸大妄想、钟情妄想、思维连贯性障碍、思维逻辑性障碍、怪异行为和冲动伤人行为等临床表型均无关联(P>0.05)；T和G等位基因频数分布分别与精神分裂症患者临床表型的各种阴性表型进行R×C表χ2检验,结果发现,rs4402960位点等位基因与思维贫乏、情感迟钝／淡漠和意志缺乏等阴性临床表型也无关联(P>0.05)。提示rs4402960位点与精神分裂症关系妄想相关联。
结论：SLC30A8基因rsl3266634位点可能与中国北方汉族人群精神分裂症发病无关联。IGF2BP2基因rs4402960位点可能与中国北方汉族人群精神分裂症发病有关联,IGF2BP2基因可能是中国北方汉族人群精神分裂症和2型糖尿病共享易感基因。
Objective:Schizophrenia is a serious mental disorder characterized by the abnormal mental functions and disturbed behaviors, which characteristically appears as a series of clinical features, such as positive and negative symptoms, and disturbances in basic cognitive functions. It belongs to complex diseases and its cause remains unknown. It is quite imperative to establish a procedure of treating and preventing schizophrenia, since the illness causes heavy economical and social burdens to families and societies. Type 2 diabetes mellitus is one of the important diseases threatening human Health in the world at present and is an important risk factor for many diseases. Up to now its pathogenesy is not clear. It is thought to be a complication that results from an interaction between genetic back ground and environmental factors now.
Over the past decade, serious efforts have been put into the search for T2DM susceptibility genes, but progress has been slower than anticipated. Recently, significant progress of T2DM susceptibility gene studies was made by genome-wide association studies (GWAS) which have identified common variants in CDKAL1, CDKN2A/B, IGF2BP2, SLC30A8, HHEX, PPARG, KCNJ11, EXT2 and LOC 387761 loci that significantly increase risk of T2DM in several studies of European descents. But the contributions of these genetic variants in other ethnic groups are less clear. In parent study, we aimed to elucidate the genetic association between IGF2BP2, SLC30A8 gene polymorphisms and schizophrenia in a Han descent population in the north of China.
Methods:Genomic DNA was isolated from the whole blood samples. A single nucleotide polymorphism, rs4402960 present in the IGF2BP2 gene and rs 13266634 present in the SLC30A8, was detected using PCR-based restriction fragment length polymorphism (PCR-RFLP) analysis among 790 Chinese Han patients with schizophrenia and 1083 ethnicity-matched healthy controls. The Hardy-Weinberg equilibrium for genotypic distribution was estimated by the goodness-of-fitχ2 test. The relationship between frequencies of alleles and genotypes of SNPs and schizophrenia and its clinical phenotypes were statistically computed.
Results:The goodness-of-fitχ2 test showed that the genotypic distributions of rs13266634 did not deviate from Hardy-Weinberg equilibrium in both patient group and control group (P>0.05). Theχ2 test did not show allelic association and genotypic association for rs13266634 (P>0.05). There were no correlations between allelic or genotypic frequencies and the clinical phenotypes of schizophrenia (P>0.05)
The goodness-of-fitχ2 test showed that the genotypic distributions of rs4402960 did not deviate from Hardy-Weinberg equilibrium in both patient group and control group (P>0.05). Theχ2 test show allelic association for rs4402960 (χ2=7.056, P= 0.008) and show genotypic association for rs4402960 (χ2=7.316, P=0.026). There were no correlations except for delusion of observation (χ2=4.145, P=0.042) between allelic or genotypic frequencies and the clinical phenotypes of schizophrenia (P>0.05)
Conclusion:The SLC30A8 locus may not be associated with schizophrenia, IGF2BP2 locus may be associated with schizophrenia and it may be a shared susceptibility gene in Chinese Han population.
方法：收集790例中国北方汉族精神分裂症患者和1083例健康人对照组全血样品,从中提取基因组DNA,采用聚合酶链式反应-限制性片段长度多态性(PCR-RFLP)的方法,检测IGF2BP2基因rs4402960位和SLC30A8基因rsl3266634位点基因型。应用拟合优度χ2检验分析基因型频数分布是否符合Hardy-Weinberg平衡定律,应用χ2检验和数量性状分析分别进行等位基因、基因型以及各种临床表型的关联性分析。
结果：SLC30A8基因rsl3266634位点的基因型频数分布在精神分裂症病例组和对照组均符合Hardy-Weinberg平衡定律(P>0.05)。等位基因关联分析表明,C和T等位基因在病例组和对照组中的频数分布比较差异无显著性(P>0.05)；基因型关联分析表明,C/C、C/T和糖尿病T/T 3种基因型在病例组和对照组的频数分布比较差异无显著性(P>0.05)；等位基因、基因型频数分布与精神分裂症各种临床表型均无关联(P>0.05)。
IGF2BP2基因rs4402960位点的基因型频数分布在精神分裂症病例组和对照组均符合Hardy-Weinberg平衡定律(P>0.05)。等位基因关联分析表明,T和G等位基因在病例组和对照组中的频数分布比较,二者差异显著(χ2=7.056,P=0.008)；基因型关联分析表明,T/T、T/G和G/G 3种基因型在病例组和对照组的频数分布比较,二者也差异显著(χ2=7.316,P=0.026),提示rs4402960位点与精神分裂症发病相关联；等位基因和精神分裂症临床表型的关联性分析在精神分裂症病例组中,rs4402960位点的T和G等位基因频数分布分别与精神分裂症患者临床表型的各种阳性症状进行4格表χ2检验。结果发现,rs4402960位点等位基因只与关系妄想相关联(χ2=4.145,P=0.042),而与真性听幻觉、影响妄想、自责自罪妄想、虚无妄想、读心症、被害妄想、嫉妒妄想、夸大妄想、钟情妄想、思维连贯性障碍、思维逻辑性障碍、怪异行为和冲动伤人行为等临床表型均无关联(P>0.05)；T和G等位基因频数分布分别与精神分裂症患者临床表型的各种阴性表型进行R×C表χ2检验,结果发现,rs4402960位点等位基因与思维贫乏、情感迟钝／淡漠和意志缺乏等阴性临床表型也无关联(P>0.05)。提示rs4402960位点与精神分裂症关系妄想相关联。
结论：SLC30A8基因rsl3266634位点可能与中国北方汉族人群精神分裂症发病无关联。IGF2BP2基因rs4402960位点可能与中国北方汉族人群精神分裂症发病有关联,IGF2BP2基因可能是中国北方汉族人群精神分裂症和2型糖尿病共享易感基因。
Objective:Schizophrenia is a serious mental disorder characterized by the abnormal mental functions and disturbed behaviors, which characteristically appears as a series of clinical features, such as positive and negative symptoms, and disturbances in basic cognitive functions. It belongs to complex diseases and its cause remains unknown. It is quite imperative to establish a procedure of treating and preventing schizophrenia, since the illness causes heavy economical and social burdens to families and societies. Type 2 diabetes mellitus is one of the important diseases threatening human Health in the world at present and is an important risk factor for many diseases. Up to now its pathogenesy is not clear. It is thought to be a complication that results from an interaction between genetic back ground and environmental factors now.
Over the past decade, serious efforts have been put into the search for T2DM susceptibility genes, but progress has been slower than anticipated. Recently, significant progress of T2DM susceptibility gene studies was made by genome-wide association studies (GWAS) which have identified common variants in CDKAL1, CDKN2A/B, IGF2BP2, SLC30A8, HHEX, PPARG, KCNJ11, EXT2 and LOC 387761 loci that significantly increase risk of T2DM in several studies of European descents. But the contributions of these genetic variants in other ethnic groups are less clear. In parent study, we aimed to elucidate the genetic association between IGF2BP2, SLC30A8 gene polymorphisms and schizophrenia in a Han descent population in the north of China.
Methods:Genomic DNA was isolated from the whole blood samples. A single nucleotide polymorphism, rs4402960 present in the IGF2BP2 gene and rs 13266634 present in the SLC30A8, was detected using PCR-based restriction fragment length polymorphism (PCR-RFLP) analysis among 790 Chinese Han patients with schizophrenia and 1083 ethnicity-matched healthy controls. The Hardy-Weinberg equilibrium for genotypic distribution was estimated by the goodness-of-fitχ2 test. The relationship between frequencies of alleles and genotypes of SNPs and schizophrenia and its clinical phenotypes were statistically computed.
Results:The goodness-of-fitχ2 test showed that the genotypic distributions of rs13266634 did not deviate from Hardy-Weinberg equilibrium in both patient group and control group (P>0.05). Theχ2 test did not show allelic association and genotypic association for rs13266634 (P>0.05). There were no correlations between allelic or genotypic frequencies and the clinical phenotypes of schizophrenia (P>0.05)
The goodness-of-fitχ2 test showed that the genotypic distributions of rs4402960 did not deviate from Hardy-Weinberg equilibrium in both patient group and control group (P>0.05). Theχ2 test show allelic association for rs4402960 (χ2=7.056, P= 0.008) and show genotypic association for rs4402960 (χ2=7.316, P=0.026). There were no correlations except for delusion of observation (χ2=4.145, P=0.042) between allelic or genotypic frequencies and the clinical phenotypes of schizophrenia (P>0.05)
Conclusion:The SLC30A8 locus may not be associated with schizophrenia, IGF2BP2 locus may be associated with schizophrenia and it may be a shared susceptibility gene in Chinese Han population.
引文
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