Chiu Y F, McGrath J A, Thornquist M H, Wolyniec P S, Nestadt G, Swartz K L, Lasseter V K, Liang K Y, Pulver A E
Department of Biostatistics, University of North Carolina, Chapel Hill, NC, USA.
Mol Psychiatry. 2002;7(6):658-64. doi: 10.1038/sj.mp.4001045.
Information from multiple genome scans and collaborative efforts suggests that schizophrenia is a heterogeneous, complex disorder with polygenic and environmental antecedents. In a previous paper we demonstrated that stratification of families on the basis of co-segregating phenotypes (psychotic affective disorders (PAD) and schizophrenia spectrum personality disorders (SSPD) in first-degree relatives of schizophrenic probands increased linkage evidence in the chromosome 8p21 region (D8S1771) among families with co-segregating SSPD. We have now applied a method of conditional analysis of sib-pairs affected with schizophrenia, examining shared alleles identical-by-descent (IBD) at multiple loci. The method yields enhanced evidence for linkage to the chromosome 8p21 region conditioned upon increased allele sharing at a chromosome 14 region. The method produces a more refined estimate of the putative disease locus on chromosome 8p21, narrowing the region from 18 cM (95% confidence interval) in our previous genome scan, to approximately 9.6 cM. We have also shown that the affected siblings sharing two alleles IBD at the chromosome 8p21 region and one allele IBD at the chromosome 14 region differ significantly in clinical symptoms from non-sharing affected siblings. Thus the analysis of allele sharing at a putative schizophrenia susceptibility locus conditioned on allele sharing at other loci provides another important method for dealing with heterogeneity.
来自多项全基因组扫描和合作研究的信息表明，精神分裂症是一种具有多基因和环境因素的异质性复杂疾病。在之前的一篇论文中，我们证明，根据共同分离的表型（精神分裂症先证者一级亲属中的精神病性情感障碍（PAD）和精神分裂症谱系人格障碍（SSPD））对家系进行分层，增加了在共同分离SSPD的家系中8号染色体p21区域（D8S1771）的连锁证据。我们现在应用了一种对精神分裂症患者同胞对进行条件分析的方法，检测多个位点上通过血缘相同的共享等位基因（IBD）。该方法在14号染色体区域等位基因共享增加的条件下，得出了与8号染色体p21区域连锁的增强证据。该方法对8号染色体p21上假定的疾病位点进行了更精确的估计，将区域从我们之前全基因组扫描中的18厘摩（95%置信区间）缩小到约9.6厘摩。我们还表明，在8号染色体p21区域共享两个IBD等位基因且在14号染色体区域共享一个IBD等位基因的患病同胞在临床症状上与不共享的患病同胞有显著差异。因此，在假定的精神分裂症易感位点上基于其他位点的等位基因共享来分析等位基因共享，为处理异质性提供了另一种重要方法。
