NRSF基因和SNAP-25基因多态性与人脑认知能力的相关性研究
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摘要
认知能力是人类在进化过程中形成的适应和改造环境的基本能力,它是人脑加工储存、提取和运用信息的能力。人类认知能力中的生物性成份是受多基因影响的,研究证明人类认知能力的遗传度为40%-80%。因此,开展影响神经系统发育和中枢神经系统活动的有关基因多态性与认知能力关系的研究对于寻找影响人类认知能力的基因有重要的意义。
神经限制性沉默因子(NRSF)因在神经系统中调控很多神经特异性基因的表达,受到国内外神经生物学家的广泛关注。目前,有关NRSF基因的报道也多集中在它对神经系统相关基因表达的调控机制方面。近年来,随着对NRSF研究的深入,发现它与人类的认知能力有相关性,且有研究表明,NRSF与受其调控的基因在对人类认知能力的影响上有联合作用。突触体相关蛋白(SNAP-25)基因是受NRSF调控的基因之一,研究表明,SNAP-25与注意缺陷多动症、精神分裂症和癫痫病有相关性。目前虽然可以查阅到NRSF和SNAP-25与人类认知能力关系的报道,但有关的报道均为欧洲人群,尚未见到NRSF和SNAP-25基因多态性与年轻健康中国汉族人群认知能力关系的报道,并且也未见到NRSF和SNAP-25基因的联合作用与人类认知能力关系的报道。
为了研究NRSF和SNAP-25基因多态性与年轻健康中国汉族人群认知能力的关系,本研究在NRSF上选择了VNTR和rs2228991两个多态位点,在SNAP-25选择了rs362584和rs3746544两个多态位点。单位点分析的结果表明,VNTR与人类认知能力的阅读工作记忆的反应时(p=0.01)和长时记忆的数字再认能力(p=0.01)有相关性,SNAP-25与言语认知能力的语音流畅性(p=0.02)和句图匹配的反应时(p=0.02)有相关性；两基因联合作用与认知能力的相关性分析结果显示,NRSF*SNAP-25基因与数字工作记忆的反应时、长时记忆的数字再认能力、言语认知能力的语音流畅性和句图匹配的反应时有相关性。
本研究的结果提示,NRSF和SNAP-25基因与年轻健康中国汉族人群认知能力具有显著相关性,NRSF和SNAP-25基因联合作用对年轻健康中国汉族人群认知能力有影响。但是,这一初步结论尚需做进一步的研究和探讨。
Cognitive ability is a basic capability of human to adapt and modify the environment formed in the course of human evolution, associating with the ability of human brain to process, storage and retrieve information. Human cognitive ability is affected by multi-gene. Studies have shown that the heritability of human cognitive abilities is 40%-80%. Therefore, it is very important to explore the relationship between genes and cognitive ability and to find genes that affect cognitive abilities through studying the relationship of polymorphism and cognitive ability.
Neural-Restrictive Silencer Factor (NRSF) attracted many neurobiologists'attention both at home and abroad, due to its regulating many neural-specific genes'express in the nervous system. So far, reports about NRSF gene has been concentrating on its regulatory mechanism of gene express in nervous system. Recent studies showed that NRSF was correlated with the human cognitive ability, and forthermore NRSF had a combined effect on human cognitive ability with genes which were regulated by it. Synaptosomal-Associated Protein gene is one of the genes regulated by NRSF, which was proved to be associated with attention deficit hyperactivity disorder, schizophrenia and epilepsy. Until now, although we can find the articles about the relationship between NRSF, SNAP-25 and human cognitive abilities, the relative reports are all about the European population. Neither the association between NRSF and SNAP-25 gene polymorphisms and cognitive ability in healthy Chinese Han population, nor the association between combined effect of NRSF and SNAP-25 gene and cognitive ability in human cognitive ability has been reported.
In order to study the relationship between NRSF and SNAP-25 gene polymorphism and cognitive ability in young healthy Chinese Han population, VNTR and rs2228991 polymorphic locus in NRSF gene, rs362584 and rs3746544 polymorphic locus in SNAP-25 gene were selected. Single locus analysis showed that VNTR of NRSF was significantly associated with react time of reading working memory (p=0.01) and digital recognition of long-term memory (p=0.01), and SNAP-25 was significantly associated with phonological fluency(p=0.02) and react time of sentence-charting matching (p=0.02). Combined analysis indicated that NRSF* SNAP-25 was significantly associated with react time of digital working memory, digital recognition of long-term memory, phonological fluency and react time of sentence-charting matching.
The above results revealed a positive association between the genetic variants of NRSF and SNAP-25 and cognitive ability in the young healthy Chinese Han population, and NRSF and SNAP-25 had a combine effect on the cognitive ability of young healthy Chinese Han population. However, this preliminary conclusion still needs further research and discussion.
神经限制性沉默因子(NRSF)因在神经系统中调控很多神经特异性基因的表达,受到国内外神经生物学家的广泛关注。目前,有关NRSF基因的报道也多集中在它对神经系统相关基因表达的调控机制方面。近年来,随着对NRSF研究的深入,发现它与人类的认知能力有相关性,且有研究表明,NRSF与受其调控的基因在对人类认知能力的影响上有联合作用。突触体相关蛋白(SNAP-25)基因是受NRSF调控的基因之一,研究表明,SNAP-25与注意缺陷多动症、精神分裂症和癫痫病有相关性。目前虽然可以查阅到NRSF和SNAP-25与人类认知能力关系的报道,但有关的报道均为欧洲人群,尚未见到NRSF和SNAP-25基因多态性与年轻健康中国汉族人群认知能力关系的报道,并且也未见到NRSF和SNAP-25基因的联合作用与人类认知能力关系的报道。
为了研究NRSF和SNAP-25基因多态性与年轻健康中国汉族人群认知能力的关系,本研究在NRSF上选择了VNTR和rs2228991两个多态位点,在SNAP-25选择了rs362584和rs3746544两个多态位点。单位点分析的结果表明,VNTR与人类认知能力的阅读工作记忆的反应时(p=0.01)和长时记忆的数字再认能力(p=0.01)有相关性,SNAP-25与言语认知能力的语音流畅性(p=0.02)和句图匹配的反应时(p=0.02)有相关性；两基因联合作用与认知能力的相关性分析结果显示,NRSF*SNAP-25基因与数字工作记忆的反应时、长时记忆的数字再认能力、言语认知能力的语音流畅性和句图匹配的反应时有相关性。
本研究的结果提示,NRSF和SNAP-25基因与年轻健康中国汉族人群认知能力具有显著相关性,NRSF和SNAP-25基因联合作用对年轻健康中国汉族人群认知能力有影响。但是,这一初步结论尚需做进一步的研究和探讨。
Cognitive ability is a basic capability of human to adapt and modify the environment formed in the course of human evolution, associating with the ability of human brain to process, storage and retrieve information. Human cognitive ability is affected by multi-gene. Studies have shown that the heritability of human cognitive abilities is 40%-80%. Therefore, it is very important to explore the relationship between genes and cognitive ability and to find genes that affect cognitive abilities through studying the relationship of polymorphism and cognitive ability.
Neural-Restrictive Silencer Factor (NRSF) attracted many neurobiologists'attention both at home and abroad, due to its regulating many neural-specific genes'express in the nervous system. So far, reports about NRSF gene has been concentrating on its regulatory mechanism of gene express in nervous system. Recent studies showed that NRSF was correlated with the human cognitive ability, and forthermore NRSF had a combined effect on human cognitive ability with genes which were regulated by it. Synaptosomal-Associated Protein gene is one of the genes regulated by NRSF, which was proved to be associated with attention deficit hyperactivity disorder, schizophrenia and epilepsy. Until now, although we can find the articles about the relationship between NRSF, SNAP-25 and human cognitive abilities, the relative reports are all about the European population. Neither the association between NRSF and SNAP-25 gene polymorphisms and cognitive ability in healthy Chinese Han population, nor the association between combined effect of NRSF and SNAP-25 gene and cognitive ability in human cognitive ability has been reported.
In order to study the relationship between NRSF and SNAP-25 gene polymorphism and cognitive ability in young healthy Chinese Han population, VNTR and rs2228991 polymorphic locus in NRSF gene, rs362584 and rs3746544 polymorphic locus in SNAP-25 gene were selected. Single locus analysis showed that VNTR of NRSF was significantly associated with react time of reading working memory (p=0.01) and digital recognition of long-term memory (p=0.01), and SNAP-25 was significantly associated with phonological fluency(p=0.02) and react time of sentence-charting matching (p=0.02). Combined analysis indicated that NRSF* SNAP-25 was significantly associated with react time of digital working memory, digital recognition of long-term memory, phonological fluency and react time of sentence-charting matching.
The above results revealed a positive association between the genetic variants of NRSF and SNAP-25 and cognitive ability in the young healthy Chinese Han population, and NRSF and SNAP-25 had a combine effect on the cognitive ability of young healthy Chinese Han population. However, this preliminary conclusion still needs further research and discussion.
引文
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[2]Bartels M., Rietveld M. J., Van Baal G. C., et al. Genetic and environmental influences on the development of intelligence[J]. Behavior genetics,2002,32(4):237-249.
[3]Mcgue M., Bouchard T. J., Iacono W. G., et al. Behavioral genetics of cognitive ability:a life-span perspective[J]. Nature Nurture Psychol,1993,59-76.
[4]Plomin R. T., L. A. Genetics and high cognitive ability[J]. Ciba Found Symp,1993,178: 79-84.
[5]Posthuma D. The Association between Brain Volume and Intelligence Is of Genetic Origin[J]. Neurosci,2002,5:83-84.
[6]Benyamin B. Large, Consistent Estimates of the Heritability of Cognitive Ability in Two Entie Populations of 11-Year-Old Twins from Scottish Mental Surveys of 1932 and 1947[J]. Behavior genetics,2005,35:525-534.
[7]Luciano M. Genome-Wide Scan of IQ Finds Significant Linkage to a Quantitative Trait Locus on 2q[J]. Behavior genetics,2006 (36) 45-55.
[8]Asher J. E. A. Whole-Genome Scan and Fine-Mapping Linkage Study of Auditory-Visual Synesthesia Reveals Evidence of Linkage to Chromosomes 2q24,5q33,6pl2,and 12p12[J]. Am J Hum Genet,84:279-285.
[9]Tsai, S., J., et al. Association Study of a Brain-Derived Neurotropic Factor(BDNF) Val66Met Polymorphism and Personality Trait and Intelligence in Healthy Young Females[J]. Neuropsychobiology,2004 49:13-16.
[10]Harris S. E. A Genetic Association Analysis of Cognitive Ability and Cognitive Aging Using 325 Markers for 109 Genes Associated with Oxidative Stress or Cognition[J], BMC Genet,2007,8:43.
[11]Egan M. F. The BDNF Val66Met Polymorphism Affects Activity-Dependent Secretion of BDNF and Human Memory and Hippocampal Function[J]. Cell,2003,112:257-269
[12]Bishop, S.J. Comt Vall58Met Genotype Affects Recruitment of Neural Mechanisms Supporting Fluid Intelligence[J]. Cereb Cortex 2008,18:2132-2140.
[13]Pritehardjk, Rosenbergna. Use of unlinked genetic markers to delect population stra-tification in assoeiation studies[J]. American journal of human genetic,199,65(1): 220-228.
[14]Wilsonjewealeme, Smithac, Gratrix. PoPulation genetic strueture of variable drug response[J]. Nature genetcs,2001,29(3):265-26.
[15]伯纳德.罗斯纳.生物统计学基础[J].北京科学出版社,2004.
[16]Schoenherr C. J., P. A. J., Anderson D J. Identification of Potential target genes for the neuron-restrictive silencer factor[J]. Proc Natl A cad Sci USA,1996,93(18):9881-9886.
[17]Bruce A. W., Donaldson I. J., Wood I. C., et al. Genome-wide analysis of repressor element 1 silencing transcription factor/neuron-restrictive silencing factor (REST/NRSF) target genes[J]. Proceedings of the National Academy of Sciences of the United States of America,2004,101(28):10458-63.
[18]Mortazavi A., Thompson E. C., Garcia, et al. Comparative genomics modeling of the NRSF/REST repressor network:from single conserved sites to genome-wide reper-toire[J]. Genome Researeh,2006,16(10):1208-1221.
[19]Grunstein M. Histone acetylation in chromatin structure and transcription[J]. Nature, 1997,389:349-352.
[20]Egan M. F. The BDNF Val66Met Polymorphism Affects Activity-Dependent Secretion of BDNF and Human Memory and Hippocampal Function[J]. Cell,2003,112:257-269
[21]Bishop, S.J. Comt Vall58Met Genotype Affects Recruitment of Neural Mechanisms Supporting Fluid Intelligence[J]. Cereb Cortex 2008,18:2132-2140.
[22]Golimbet V., Alfimova M., Gritsenko I. The association of the SNAP-25 gene polymor-phism with verbal memory and attention in patients with major psychosis and healthy people[J]. Zh Nevrol Psikhiatr Im S S Korsakova,2009,109(1):59-63.
[23]Kimia K., Najmabadi H., Kariminejad R., et al. An autosomal recessive syndrome of severe mental retardation, cataract, coloboma and kyphosis maps to the pericentromeric region of chromosome 4[J]. Eur J Genet 2009,17(1):125-128.
[24]Miyajima F., Quinn J. P., Horan M., et al. Additive effect of BDNF and REST polymor-phisms is associated with improved general cognitive ability[J]. Genes, brain, and behavior,2008,7(7):714-719.
[25]王小飞,于盼盼,陆佩华.NRSE与NRSF及其对神经元特异性基因表达的调控作用[J].生物化学与生物物理进展,2005,32(7)：595-598.
[26]Oyler G. A., Higgins G. A., Hart R. A., et al. The identification of a novel synaptosomal-associated protein, SNAP-25, differentially expressed by neuronal subpopulations[J]. The Journal of cell biology,1989,109(61):3039-3052.
[27]Sadhof, T C. The synaptic vesicle cycle:a cascade of protein interaction[J]. Nature,1995, 375:645-653.
[28]Rothman, J.E. Mechanisms of intracellar protein transport.[J]. Nature,1994,372:55-63.
[29]Grosse G., Grosse J., Tapp R., et al. SNAP-25 requirement for dendritic growth of hippocampal neurons[J]. J Neurosei Res,1999,56(5):539-546.
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