精神分裂症主要易感基因的研究进展

精神分裂症（schizophrenia,SCZ）是一种常见的、复杂的精神疾病,至今原因不明。一般认为该病是环境因素和遗传因素共同作用的结果。近年来的研究证实,遗传因素在SCZ发病过程中起着重要的作用。采用全基因组扫描与连锁分析、全基因组关联研究与连锁不平衡分析,已发现了一系列SCZ的易感基因,其中包括DTNBPl、COMT、DISCl和NRGl等。此文在简要介绍该病研究策略的同时．综述上述几种SCZ易感基因的研容讲展。     

慢性乙型肝炎易感基因的全基因组关联研究进展

慢性乙型肝炎(chronic hepatitis B,CHB)是一种由遗传、病毒与环境因素共同导致的复杂疾病,具有高度的遗传异质性。自2009年首个CHB全基因组关联研究(genome-wide association studies,GWAS)报道以来,许多GWAS相继开展。文章首先对目前发表的CHB易感基因的GWAS结果进行汇总,发现染色体6p21.32区域中CHB易感位点最多。然而目前GWAS主要基于常见变异-常见疾病原则设计,只涉及了频率≥5%的单核苷酸多态性(single nucleotide polymorphism,SNP),没有涵盖人类基因组中重要的低频变异。同时GWAS鉴定到的最显著关联的SNP大多位于内含子、基因间区等非编码区域内,导致功能学研究无法开展。乙型肝炎病毒(hepatitis B virus,HBV)功能性受体钠离子-牛磺胆酸共转运蛋白的发现,加快了HBV感染的机制研究。同时第二代测序技术的发展为CHB易感基因的发现提供了契机。因此今后的研究应将GWAS的发现与功能学研究相结合,以逐步揭示HBV感染的遗传机制。     

2型糖尿病易感位点的功能性L1逆转录转座子的研究

目的通过一种新的策略寻找2型糖尿病的易感基因.方法应用美国生物技术信息中心提供的BLAST(basic local alignment search tool)检索工具,对已报道的2型糖尿病易感位点的核酸序列进行检索分析,发现功能性L1逆转录转座子可能是易感基因.然后应用逆转录-聚合酶链反应检测25例2型糖尿病患者和22名正常对照的L1逆转录转座子表达水平,用SPSS10.0软件包进行统计学分析,并对6例患者和4名正常人的L1逆转录转座子进行定位克隆、基因组序列测定.结果对人类基因组及GenBank数据库进行全面搜索分析发现L1逆转录转座子分布在除19号、21号和Y染色体外的其它染色体上.这种分布情况与已报道的易感位点在染色体上的分布情况有相似性.功能性L1逆转录转座子在2型糖尿病患者组的表达水平明显低于正常对照组(P＜0.001).L1逆转录转座子在2型糖尿病患者有不同程度的缺失和(或)无意义突变,而在正常对照无突变.结论功能性L1逆转录转座子可能是2型糖尿病的某一易感基因或者是其易感基因的重要调节因子之一.功能性L1逆转录转座子表达水平的高低可能可以作为筛选2型糖尿病的一个生物学指标.     

过敏性疾病易感基因研究方法进展

过敏性疾病是多基因遗传和多环境因素相互影响的结果[1-3]。根据最新的世界过敏组织的报告:过敏性疾病在全球的高发病率和高死亡率给健康预算带来了巨大的负担。阐明过敏性疾病的发病机制,和提出有针对性、有效的治疗方案是迫切需要解决的问题。2001年公布人类基因组序列草图后,更多的目光聚焦在个体之间的基因组变异上,大量关于过敏性疾病易感基因的研究陆续展开。用于发现     

DNA混合池技术全基因组关联研究筛查主动脉夹层易感基因的研究

目的筛选主动脉夹层发病机制相关的遗传易感基因。方法选取主动脉夹层患者为病例组（150例）,按照性别、年龄、是否吸烟、合并高血压、糖尿病情况与病例组匹配的原则入选排除主动脉夹层、重大心血管疾病及肿瘤的志愿者为对照组（250例）,均从外周血提取基因组DNA,采用DNA混合池技术为基础的Illumina Human660W—Quad芯片扫描,筛选主动脉夹层发病相关的遗传易感基因。结果对照组女性数量明显多于病例组（P〈0．01）;在年龄、吸烟、高血压、糖尿病人数方面差异均无统计学意义（P〉0．05）。根据芯片扫描结果,挑选silhouettewidth计算值大于0．7,最小等位基因频率（MAF）大于0．05,且SNPs位于已知名称基因上的前5个SNPs位点。结果发现,遗传变异位点SNP rs2970873（位于PPARGClA基因）、SNP rs12678080（位于SGCZ基因）、SNP rs489526（位于UNCl3C基因）、SNP rs6928665（位于TRAM2基因）和SNP rs17837003（位于ACCNl基因上）可能与主动脉夹层的发病机制有关。结论SNPsrs2970873、rs12678080、rs489526、rs6928665和rsl7837003可能与主动脉夹层发病机制相关。     

中国科学家发现白癜风易感基因

由安徽医科大学张学军教授领衔的研究团队历时5年,运用全基因组关联分析研究（GWAS）成功发现了白癜风易感基因,首次在国际上明确白癜风是自身免疫性疾病,为最终征服白癜风这种复杂疾病奠定了第一步基础。     

注意缺陷多动障碍易感基因的定位与克隆研究进展

注意缺陷多动障碍易感基因的定位与克隆主要有候选基因克隆法和定位克隆法。本文系统 介绍了注意缺陷多动障碍易感基因定位克隆的研究现状和存在的问题以及解决的办法。     

焦虑障碍经济负担研究的系统评价

目的：了解国外焦虑障碍经济负担研究的状况及研究方法，为我国开展焦虑障碍经济负担研究提供理论依据。方法：计算机检索相关文献。根据研究方法的不同分为焦虑障碍人均经济负担和国家经济负担研究，将各国的研究结果转换成2006年的货币价值后，根据购买力平价统一转换成美元。结果：纳入13篇文献，其中11篇为人均经济负担研究，2篇为国家经济负担研究。焦虑障碍人均直接经济负担最低为256美元／年，最高为8829美元／年，人均间接经济负担最少为328美元，最多达到8655美元／年。只有美国进行了焦虑障碍国家经济负担的研究，约为700亿美元／年。结论：焦虑障碍给家庭和社会带来沉重的经济负担。     

Xp1区内定位注意缺损多动障碍易感位点的研究

目的探讨注意缺损多动障碍(attention deficit hyperactivity disorder, ADHD)与单胺氧化酶(monoamine oxidase, MAO)A型基因的遗传关系。方法采用基于单体型相对风险(haplotype-based haplotype relative risk,HHRR)和传递不平衡检验(transmission disequilibrium test, TDT)的方法,在60个ADHD儿童和双亲中进行了MAOCA微卫星多态性的关联和连锁分析。结果经HHRR和TDT分析,ADHD儿童与MAOCA位点114 bp相关联和连锁(χ2分别为4.90和4.84,P＜0.05)。结论 ADHD与MAO A型基因相关联和连锁,其易感位点可能定位于Xp1区。     

儿童类风湿关节炎高贡献率易感基因的研究

目的通过对小儿类风湿关节炎全基因组基因拷贝数变异(copy number variations,CNVs)的研究,为该病易感基因筛选和发病机制研究提供理论基础。方法选取小儿类风湿关节炎患者(Juvenile rheumatoid arthritis,JRA)20例作为患病组,随机从体检中心选取无类风湿关节炎患病史健康儿童20例作为健康对照组。采用测序仪分别对类风湿关节炎患病组和健康组的DNA-pool进行全基因组重测序,用生物信息学软件对测序数据进行分析。结果我们采用CNVnator软件对患病组和健康组的测序数据进行检测,发现CNV位点分别为7479个和5201个。通过生物信息学分析筛选,患病组与健康组比较发现有825个CNVs位点,其中有192个位于内含子区域,有93个位于外显子区域,19个位于上游位置,25个位于下游位置。结论本研究揭示了儿童期类风湿关节炎患者的基因组拷贝数变异的变化,并发现了编码区的KIR3DL1、CD247、PPIP5K1、MIOX、ANK3、HK3基因可能为类风湿关节炎的易感基因。     

The genetic basis of panic disorder

Panic disorder is one of the chronic and disabling anxiety disorders. There has been evidence for either genetic heterogeneity or complex inheritance, with environmental factor interactions and multiple single genes, in panic disorder's etiology. Linkage studies have implicated several chromosomal regions, but no research has replicated evidence for major genes involved in panic disorder. Researchers have suggested several neurotransmitter systems are related to panic disorder. However, to date no candidate gene association studies have established specific loci. Recently, researchers have emphasized genome-wide association studies. Results of two genome-wide association studies on panic disorder failed to show significant associations. Evidence exists for differences regarding gender and ethnicity in panic disorder. Increasing evidence suggests genes underlying panic disorder overlap, transcending current diagnostic boundaries. In addition, an anxious temperament and anxiety-related personality traits may represent intermediate phenotypes that predispose to panic disorder. Future research should focus on broad phenotypes, defined by comorbidity or intermediate phenotypes. Genome-wide association studies in large samples, studies of gene-gene and gene-environment interactions, and pharmacogenetic studies are needed.     

Genome-Wide Association Study of Lung Cancer in Korean Non-Smoking Women

Lung cancer in never-smokers ranks as the seventh most common cause of cancer death worldwide, and the incidence of lung cancer in non-smoking Korean women appears to be steadily increasing. To identify the effect of genetic polymorphisms on lung cancer risk in non-smoking Korean women, we conducted a genome-wide association study of Korean female non-smokers with lung cancer. We analyzed 440,794 genotype data of 285 cases and 1,455 controls, and nineteen SNPs were associated with lung cancer development (P < 0.001). For external validation, nineteen SNPs were replicated in another sample set composed of 293 cases and 495 controls, and only rs10187911 on 2p16.3 was significantly associated with lung cancer development (dominant model, OR of TG or GG, 1.58, P = 0.025). We confirmed this SNP again in another replication set composed of 546 cases and 744 controls (recessive model, OR of GG, 1.32, P = 0.027). OR and P value in combined set were 1.37 and < 0.001 in additive model, 1.51 and < 0.001 in dominant model, and 1.54 and < 0.001 in recessive model. The effect of this SNP was found to be consistent only in adenocarcinoma patients (1.36 and < 0.001 in additive model, 1.49 and < 0.001 in dominant model, and 1.54 and < 0.001 in recessive model). Furthermore, after imputation with HapMap data, we found regional significance near rs10187911, and five SNPs showed P value less than that of rs10187911 (rs12478012, rs4377361, rs13005521, rs12475464, and rs7564130). Therefore, we concluded that a region on chromosome 2 is significantly associated with lung cancer risk in Korean non-smoking women.     

Genetic Studies in Human Prion Diseases

Human prion diseases are fatal neurodegenerative disorders that are characterized by spongiform changes, astrogliosis, and the accumulation of an abnormal prion protein (PrP^Sc). Approximately 10%-15% of human prion diseases are familial variants that are caused by pathogenic mutations in the prion protein gene (PRNP). Point mutations or the insertions of one or more copies of a 24 bp repeat are associated with familial human prion diseases including familial Creutzfeldt-Jakob disease (CJD), Gerstmann-Sträussler-Scheinker syndrome, and fatal familial insomnia. These mutations vary significantly in frequency between countries. Here, we compare the frequency of PRNP mutations between European countries and East Asians. Associations between single nucleotide polymorphisms (SNPs) of several candidate genes including PRNP and CJD have been reported. The SNP of PRNP at codon 129 has been shown to be associated with sporadic, iatrogenic, and variant CJD. The SNPs of several genes other than PRNP have been showed contradictory results. Case-control studies and genome-wide association studies have also been performed to identify candidate genes correlated with variant and/or sporadic CJD. This review provides a general overview of the genetic mutations and polymorphisms that have been analyzed in association with human prion diseases to date.

Graphical Abstract

相似文献   

焦虑障碍者的个性倾向、特质焦虑和自我效能感

目的:通过对焦虑障碍患者个性倾向、自我效能感、特质焦虑等影响因素的相关研究,探讨焦虑障碍可能的病理心理学机制。方法:采用病例对照研究,对144例焦虑障碍患者和144名健康人利用中国人个性量表-情感量表(CPAI2-E)、状态-特质焦虑问卷(STAI)、自我效能感量表(GSES)评定。结果:①患者组情感量表的诸因子得分显著高于对照组(P<0.01);②患者组特质焦虑得分显著高于对照组,而自我效能感得分对照组高于患者组(P<0.01);③状态焦虑与情感量表各因子、特质焦虑呈正相关(r=0.459～0.781,P<0.01),与自我效能感量呈负相关(r=-0.332,P<0.01)。④多元逐步回归分析发现,特质焦虑和焦虑紧张因子与焦虑情绪的关系更为密切。结论:特质焦虑、抑郁、焦虑紧张、躯体症状、躯体化、性适应不良及自卑倾向等诸多因素间的交互作用可能是焦虑障碍发生的病理心理学基础,特质焦虑与焦虑情绪的关系更为密切。     

焦虑症患者心理控制源与应付方式的关系研究

目的研究焦虑症患者的心理控制源和应付方式特点,并探讨二者的关系。方法采用内控性、有势力的他人及机遇量表(IPC)和应付方式问卷(Cop ing S ty le Scale)对32例焦虑症患者进行评定并进行统计分析。结果①描述性统计分析结果显示,焦虑症患者的机遇心理控制源得分最高(3.48±0.82)分,其次是内控、有势力他人分别为(3.13±0.72)分和(3.04±1.02)分;②描述性统计分析结果显示,幻想、自责的应付方式得分最高分别为(0.69±0.20)分和(0.63±0.25)分,求助、合理化、解决问题的应付方式得分最低[分别为(0.43±0.16)分、(0.45±0.18)分和(0.55±0.29)分];③相关分析结果显示,焦虑症患者心理控制源与应付方式呈显著相关(P<0.05);④线性回归分析结果显示,机遇心理控制源对成熟应付方式具有显著的负向预测效果(F=4.743,P<0.01),有势力他人心理控制源对不成熟应对方式具有显著的正向预测效果(F=7.121,P<0.01),内控性和机遇心理控制源对混合型应对方式具有显著的正向预测效果(F=16.741,P<0.001)。结论焦虑症患者面临应激事件时倾向于采用不成熟的应付方式,这与其心理控制源有密切联系。     

Experiential learning in psychotherapy: ropes course exposures as an adjunct to inpatient treatment

Exposures to a high-ropes course are introduced as an adjunct intervention in the therapy of psychotherapy patients. A controlled study was conducted to investigate the effectiveness of high-ropes exposures as an add-on to inpatient treatment in a naturalistic setting. In a sample of 247 patients, depressive symptoms, trait anxiety, locus of control and self-efficacy were assessed at admission and discharge of treatment and at 24-month follow-up. Follow-up data were available for 104 patients who attended the ropes courses and 53 control patients who underwent an inpatient treatment programme as usual. At the end of treatment, more high-rope participants showed clinically significant change on trait anxiety than controls but not regarding depressive symptoms. High-rope participants showed better follow-up outcomes than controls in trait anxiety and self-efficacy but not in depressive symptoms and external locus of control. Moreover, during follow-up, in the high-rope group, more patients showed reliable improvements and fewer patients showed reliable deteriorations in trait anxiety as compared with controls. The study gives a preliminary indication that the high-rope interventions are a feasible and valuable add-on to inpatient psychotherapy. The study design, sample composition and loss to follow-up are discussed as potential limitations of the study.     

焦虑调查及其缓解与治疗研究

目的探讨师专学生的状态焦虑和特质焦虑特点及其缓解和治疗。方法采用状态一特质焦虑问卷（STAI From Y-2），随机抽取河北省定州市225名师专学生追行问卷调查。结果（1）一年级、二年级与三年级学生的状态和特质焦虑都存在顾着性差异。（2）独生和非独生学生的特质焦虑存在顾着性差异。（3）单亲和其他家庭学生的特质焦虑存在显著性差异。（4）母亲职业是工人与母亲职业是农民学生的状态和特质焦虑存在显著性差异。（5）高状态和特质焦虑分别占9．3％和8．0％，出现焦虑症特征。结论显著影响学生焦虑水平的因素有年级、是否独生、家庭结构、母亲职业。     

dbAARD & AGP: A computational pipeline for the prediction of genes associated with age related disorders

The atrocious behavioral and physiological shift with aging accelerate occurrence of deleterious disorders. Contemporary research is focused at uncovering the role of genetic associations in age-related disorders (ARDs). While the completion of the Human Genome Project and the HapMap project has generated huge amount of data on genetic variations; Genome-Wide Association Studies (GWAS) have identified genetic variations, essentially SNPs associated with several disorders including ARDs. However, a repository that houses all such ARD associations is lacking. The present work is aimed at filling this void. A database, dbAARD (database of Aging and Age Related Disorders) has been developed which hosts information on more than 3000 genetic variations significantly (p-value <0.05) associated with 51 ARDs. Furthermore, a machine learning based gene prediction tool AGP (Age Related Disorders Gene Prediction) has been constructed by employing rotation forest algorithm, to prioritize genes associated with ARDs. The tool achieved an overall accuracy in terms of precision 75%, recall 76%, F-measure 76% and AUC 0.85. Both the web resources have been made available online at http://genomeinformatics.dce.edu/dbAARD/ and http://genomeinformatics.dce.edu/AGP/ respectively for easy retrieval and usage by the scientific community. We believe that this work may facilitate the analysis of plethora of variants associated with ARDs and provide cues for deciphering the biology of aging.     

艾司西酞普兰治疗广泛性焦虑症的临床研究

目的:评价艾司西酞普兰治疗广泛性焦虑症的临床疗效和安全性。方法:对符合入组标准的广泛性焦虑症患者服用艾司西酞普兰,疗程8周,并用汉密尔顿焦虑量表(HAMA)、临床疗效总评量表(CGI)、药物不良反应评定量表(TESS)分别在治疗前、治疗第2、4、6、8周进行评分。依据HAMA总分减分率判定疗效。结果:治疗第2周起,HAMA评分,CGI评分与治疗前相比均有显著下降(p<0.01),治疗第8周有效率为80.49%。不良反应最常见的是食欲下降(14.63%),其次恶心(7.32%),但不影响正常治疗。结论:艾司西酞普兰治疗广泛性焦虑症有效、安全,不良反应轻。