dysbindin-1 gene（DTNBP1）是一种精神分裂症（schizophrenia）的易感基因，来自Feinstein医学研究院Zucker Hillside 医院（ Zucker Hillside Hospital campus of The Feinstein Institute for Medical Research）的研究人员发现这个基因实际上也是影响一般智力的关键基因。这一研究成果公布在4月27日Human Molecular Genetics杂志上。
近年来有关精神分裂症的遗传流行病学是国内外的一大研究热点。研究表明精神分裂症的发生与多巴胺受体途径、谷氨酸受体途径、或5－羟色胺等神经递质传导途径有关。因此利用相关性研究，针对这些途径中有关的基因多态位点(SNPs)与精神分裂症的相关性研究的报道越来越多，而且有一定的人群和种族差异。通过全基因组扫描，对一些精神分裂症家系的连锁分析，表明精神分裂症有多个易感基因位点存在，如定位于染色体1q,2, 6p, 8p, 13q, 22q等位点。2002年美国和冰岛的两个研究小组分别报道定位于6p22.3的 DTNBP1基因和8p12-21的 NRG1 基因可能是精神分裂症的易感基因，然而Katherine Burdick等人通过对213个精神分裂症白种人和126个健康自愿者进行了认知行为的检测，在DTNBP1中发现了6个DNA变异——单核苷酸多态性SNPs (single nucleotide polymorphisms)，其中一个和认知能力相关的。因此研究人员认为DTNBP1在大脑细胞交流过程中扮演了一个重要的角色：帮助提升细胞存活度。
原始出处：
http://hmg.oxfordjournals.org/cgi/content/abstract/ddi481v1
有关DTNBP1基因与精神疾病
The DTNBP1 (Dysbindin) Gene Contributes to Schizophrenia,
Depending on Family History of Disease
David Werny
Rollins School of Public Health, Emory University
The Health Outcome
Schizophrenia is a highly debilitating mental illness characterized by episodes of psychotic hallucinations often accompanied by severe depression. Episodes are commonly precipitated by psychologically stressful events, implying a possible measurable gene-environment interaction. Worldwide prevalence is estimated to be 1%. Hypothesized risk-factors that have been previously identified include high paternal age, fetal oxygen deprivation, previous head injuries, maternal stress during pregnancy, having a winter birthday (believed associated with maternal viral infection before third trimester), and ‘disruptive environments’, including drug or sexual abuse (1). Previous studies, including many twin studies, show a strong genetic component for susceptibility, specifically finding linkage with chromosomes 3, 6, 8, and 21, and other genetic elements, notably a deletion at 22q11.2 (1). DTNBP1, the gene studied here, is located on chromosome 6, and codes for dysbindin, a protein found in rat brain and muscle tissue. Yet untested hypotheses suggest a role for dysbindin in neuronal signal transduction (2). Previous studies have found linkage with DTNBP1 in Irish pedigrees (3) as well as German, Israeli, and Hungarian families (4). No association was found in an Irish population-based study (5). The purpose of the current study is to confirm the results with data from Swedish, Polish, and German samples.
The Finding
This German, Polish, and Swedish population-based case-control study examined 5 SNPs and found several 2, 3, 4, and 5 marker haplotypes significantly more often among cases than controls. Significant findings were entirely restricted to Swedish participants and mostly to those having a family history of schizophrenia. Specific 5 marker haplotypes were examined in Swedish samples with a family history of schizophrenia and one (ACATT) was found in 17.8% of cases and 3.1% of controls, yielding an odds ratio of 6.75. All of the SNPs studied were located in introns of the 140 kb DTNBP1 gene, making the biological effect of the SNPs unclear. The authors rei tera te the importance of examining family history in such studies (6).
Public Health Implications
In the future, such a gene may provide testable SNPs for risk assessment of familial schizophrenia. More immediately, this study adds weight to the argument for a genetic linkage for schizophrenia. Future biochemical studies may elaborate on this finding by considering variation both in the coding sequences of DTNBP1, and in the functionality of the protein product in both cases and controls. In this way the van den Bogaert paper may stimulate fruitful research in the biological mechanisms of the disease, hopefully leading to discoveries of new anti-psychotics.
However, the restriction of most significant results to ‘family history’ cases limits extrapolation and suggests a distinction should be made between non-family history and family-history schizophrenia. In a broader sense, the different results seen in the Swedish, German, Polish cohorts also imply population level differences in etiology and perhaps even in the type of disease. Still, a discrepancy in the diagnosis criteria between the three groups reveals that the differences may be an artifact of the study itself. The Swedish group was less restrictive when determining cases (two weeks of symptoms, rather than four in the German and Polish groups), and this may have biased the results.
References
Walker E, et al. (2004) Schizophrenia: Etiology and Course. Annu Rev Psychol 55: 401-430.
Benson M., et al. (2001) Dysbindin, a Novel Coiled-coil containing Protein That Interacts with the Dystrobrevins in Muscle and Brain. J Biol Chem 276: 24232-24241.
Straub RE, et al. (2002) Genetic Variation in the 6p22.3 gene DTNBP1, the Human Ortholog of the Mouse Dysbindin Gene is Associated with Schizophrenia. Am J Hum Genet 71: 337-348.
Schwab SG, et al. (2003) Support for the Association of Schizophrenia with Genetic Variation in the 6p22.3 Gene Dysbindin in Sib-pair Families with Linkage and in an Additional Sample of Triad Families. Am J Hum Genet 72:185-190.
Morris DW, et al. (2003) No Evidence for Association of the Dysbindin Gene (DTNBP1) with Schizophrenia in an Irish Population-based Study. Schizoph. Res 60: 167-172.
Van Den Bogaert A., et al. (2003) The DTNBP1 (Dysbindin) Gene Contributes to Schizophrenia, Depending on Family History of the Disease. Am J Hum Genet Dec; 73(6): 1438-1443.
