Zuo Lingjun, Luo Xingguang, Kranzler Henry R, Lu Lingeng, Rosenheck Robert A, Cramer Joyce, van Kammen Daniel P, Erdos Joseph, Charney Dennis S, Krystal John, Gelernter Joel
Department of Psychiatry, Yale University School of Medicine, New Haven, CT 06516, USA.
Psychiatr Genet. 2009 Dec;19(6):292-304. doi: 10.1097/ypg.0b013e32832a50bc.
Straub et al. (2002b) located a susceptibility region for schizophrenia at the DTNBP1 locus. At least 40 studies (including one study in US populations) attempted to replicate this original finding, but the reported findings are highly diverse and at least five pathways by which dysbindin protein might be involved in schizophrenia have been proposed. This study aimed to test the association in two common US populations by using powerful analytic methods.
Six markers at DTNBP1 were genotyped by mass spectroscopy ('MassARRAY' technique) in a sample of 663 individuals, including 346 healthy individuals European-Americans (EAs) and 48 African-Americans (AAs), and 317 individuals with schizophrenia (235 EAs and 82 AAs). Thirty-eight ancestry-informative markers were genotyped in this sample to infer the ancestry proportions. Diplotype, haplotype, genotype, and allele frequency distributions were compared between the cases and controls, controlling for possible population stratification, admixture, and sex-specific effects, and taking interaction effects into account, using a logistic regression analysis (an extended structured association method).
Conventional case-control comparisons showed that genotypes of the markers P1578 (rs1018381) and P1583 (rs909706) were nominally associated with schizophrenia in EAs and in AAs, respectively. These associations became less or nonsignificant after controlling for population stratification and admixture effects (using structured association or regression analysis), and became nonsignificant after correction for multiple testing. However, regression analysis showed that the common diplotypes (ACCCTT/GCCGCC or GCCGCC/GCCGCC) and the interaction effects of haplotypes GCCGCC/GCCGCC significantly affected risk for schizophrenia in EAs, effects that were modified by sex. Fine-mapping using d or J statistics located the specific markers (d: P1328; J: P1333) closest to the putative risk sites in EAs.
This study shows that DTNBP1 is a risk gene for schizophrenia in EAs. Variation at DTNBP1 may modify risk for schizophrenia in this population.
施特劳布等人（2002年b）在DTNBP1基因座定位了一个精神分裂症易感区域。至少40项研究（包括一项针对美国人群的研究）试图重复这一最初发现，但报告的结果差异很大，并且已经提出了至少五种dysbindin蛋白可能参与精神分裂症的途径。本研究旨在通过使用强大的分析方法来检验两个常见美国人群中的关联性。
采用质谱法（“MassARRAY”技术）对DTNBP1基因座的六个标记进行基因分型，样本包括663名个体，其中有346名健康的欧洲裔美国人（EA）和48名非裔美国人（AA），以及317名精神分裂症患者（235名EA和82名AA）。在该样本中对38个祖先信息标记进行基因分型以推断祖先比例。使用逻辑回归分析（一种扩展的结构化关联方法），比较病例组和对照组之间的双倍型、单倍型、基因型和等位基因频率分布，同时控制可能的群体分层、混合和性别特异性效应，并考虑交互效应。
传统的病例对照比较显示，标记P1578（rs1018381）和P1583（rs909706）的基因型分别在EA和AA中与精神分裂症存在名义上的关联。在控制群体分层和混合效应后（使用结构化关联或回归分析），这些关联减弱或变得不显著，在进行多重检验校正后变得不显著。然而，回归分析表明，常见的双倍型（ACCCTT/GCCGCC或GCCGCC/GCCGCC）以及单倍型GCCGCC/GCCGCC的交互效应显著影响EA中精神分裂症的风险，且这些效应受性别影响。使用d或J统计量进行精细定位，确定了EA中最接近假定风险位点的特定标记（d：P13２8；J：P1333）。
本研究表明DTNBP1是EA中精神分裂症的一个风险基因。DTNBP1基因的变异可能会改变该人群中精神分裂症的风险。
