A Reanalysis of 409 European-Ancestry and African American Schizophrenia Pedigrees Reveals Significant Linkage to 8p23.3 With Evidence of Locus Heterogeneity
A Reanalysis of 409 European-Ancestry and African American Schizophrenia Pedigrees Reveals Significant Linkage to 8p23.3 With Evidence of Locus Heterogeneity
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DOI：
10.1002/ajmg.b.30722
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发表时间：
2008-10-05
影响因子：
2.8
通讯作者：
Nyholt, D. R.
中科院分区：
文献类型：
--
作者：
Holliday, E. G.;Mowry, B. J.;Nyholt, D. R.
精神分裂症风险位点的检测和复制可能需要大量的样本量，这促使各种合作努力将多个样本结合起来。然而，合并样本可能包含具有大量群体遗传差异的子样本，包括等位基因频率差异。我们通过对精神分裂症1型分子遗传学（MGS1）影响的兄弟姐妹数据的连锁再分析，研究了群体差异的影响，包括两个不同祖先起源的样本：欧洲人（EA: 263个谱系）和非洲裔美国人（AA: 146个谱系）。为了利用这些不同大陆样本中包含的连锁信息，我们对单个样本进行了单独的分析，考虑了样本内基因座异质性，并对合并样本进行了分析，考虑了样本内和样本间的异质性。经多次检验校正后的显著性水平是经验性的。对于所有提示性峰值，无论如何为后者建模异质性，EA或AA样本中的关联证据都比组合样本强。值得注意的是，我们报告了精神分裂症与8p23.3的全基因组显著联系，并有证据表明，在8p21.3上有第二个独立的易感位点，达到29 cM远的暗示联系。我们还在染色体5p13.3和7q36.2上检测到暗示性连锁。许多地区在EA和AA样品之间的联系程度上显示出明显的差异。这一重新分析强调了汇总数据中种群差异对关联证据的潜在影响，并为分析来自不同大陆群体的样本展示了一种有用的方法。(C) 2008 Wiley-Liss, Inc。
The detection and replication of schizophrenia risk loci can require substantial sample sizes, which has prompted various collaborative efforts for combining multiple samples. However, pooled samples may comprise sub-samples with substantial population genetic differences, including allele frequency differences. We investigated the impact of population differences via linkage reanalysis of Molecular Genetics of Schizophrenia 1 (MGS1) affected sibling-pair data, comprising two samples of distinct ancestral origin: European (EA: 263 pedigrees) and African-American (AA: 146 pedigrees). To exploit the linkage information contained within these distinct continental samples, we performed separate analyses of the individual samples, allowing for within-sample locus heterogeneity, and the pooled sample, allowing for both within-sample and between-sample heterogeneity. Significance levels, corrected for the multiple tests, were determined empirically. For all suggestive peaks, stronger linkage evidence was obtained in either the EA or AA sample than the combined sample, regardless of how heterogeneity was modeled for the latter. Notably, we report genomewide significant linkage of schizophrenia to 8p23.3 and evidence for a second, independent susceptibility locus, reaching suggestive linkage, 29 cM away on 8p21.3. We also detected suggestive linkage on chromosomes 5p13.3 and 7q36.2. Many regions showed pronounced differences in the extent of linkage between the EA and AA samples. This reanalysis highlights the potential impact of population differences upon linkage evidence in pooled data and demonstrates a useful approach for the analysis of samples drawn from distinct continental groups. (C) 2008 Wiley-Liss, Inc.