dysbindin-1  gene（DTNBP1）是一種精神分裂癥（schizophrenia）的易感基因，來自Feinstein醫(yī)學(xué)研究院Zucker  Hillside  醫(yī)院（  Zucker  Hillside  Hospital  campus  of  The  Feinstein  Institute  for  Medical  Research）的研究人員發(fā)現(xiàn)這個基因?qū)嶋H上也是影響一般智力的關(guān)鍵基因,。這一研究成果公布在4月27日Human  Molecular  Genetics雜志上,。

        近年來有關(guān)精神分裂癥的遺傳流行病學(xué)是國內(nèi)外的一大研究熱點(diǎn)。研究表明精神分裂癥的發(fā)生與多巴胺受體途徑,、谷氨酸受體途徑,、或5－羥色胺等神經(jīng)遞質(zhì)傳導(dǎo)途徑有關(guān)。因此利用相關(guān)性研究,，針對這些途徑中有關(guān)的基因多態(tài)位點(diǎn)(SNPs)與精神分裂癥的相關(guān)性研究的報道越來越多,，而且有一定的人群和種族差異。通過全基因組掃描,，對一些精神分裂癥家系的連鎖分析,，表明精神分裂癥有多個易感基因位點(diǎn)存在，如定位于染色體1q,2,  6p,  8p,  13q,  22q等位點(diǎn),。2002年美國和冰島的兩個研究小組分別報道定位于6p22.3的  DTNBP1基因和8p12-21的  NRG1  基因可能是精神分裂癥的易感基因,，然而Katherine  Burdick等人通過對213個精神分裂癥白種人和126個健康自愿者進(jìn)行了認(rèn)知行為的檢測，在DTNBP1中發(fā)現(xiàn)了6個DNA變異——單核苷酸多態(tài)性SNPs  (single  nucleotide  polymorphisms),，其中一個和認(rèn)知能力相關(guān)的,。因此研究人員認(rèn)為DTNBP1在大腦細(xì)胞交流過程中扮演了一個重要的角色：幫助提升細(xì)胞存活度。

原始出處：

http://hmg.oxfordjournals.org/cgi/content/abstract/ddi481v1

有關(guān)DTNBP1基因與精神疾病

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.