Identity-by-descent mapping to detect rare variants conferring susceptibility to multiple sclerosis.
Identity-by-descent mapping to detect rare variants conferring susceptibility to multiple sclerosis.
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逐渐映射的身份映射以检测稀有变体，赋予多发性硬化症的敏感性。
DOI：
10.1371/journal.pone.0056379
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Taylor BV
中科院分区：
文献类型：
--
作者：
Lin R;Charlesworth J;Stankovich J;Perreau VM;Brown MA;ANZgene Consortium;Taylor BV
全基因组关联研究 (GWAS) 已识别出大约 60 个与多发性硬化症 (MS) 相关的常见变异，但这些位点只能解释 MS 遗传性的一小部分。一些遗传性缺失可能是由罕见变异引起的，这些变异被认为在多发性硬化症等复杂疾病的病因学中发挥着重要作用。然而，目前用于检测罕见变异的遗传和统计方法既昂贵又耗时。 “基于群体的连锁分析”（PBLA）或所谓的血统身份（IBD）映射是一种检测现有 GWAS 数据集中罕见变异的新方法。我们利用 BEAGLE fastIBD 在包含 3,543 例病例和 5,898 例对照的大型 GWAS 数据集中利用 IBD 映射来搜索罕见的 MS 变异。我们在 19 号染色体上发现了一个全基因组显着连锁信号（LOD = 4.65；p = 1.9×10−6）。对 19 号染色体上共享单倍型的病例和对照的网络分析进一步加强了这种关联，因为共享单倍型的病例网络比对照有更多的大型网络。该连锁区包括一簇功能未知的锌指基因。对全基因组转录组数据的分析表明，该锌指簇中的基因可能参与中枢神经系统的早期发育调控。我们的研究还表明，BEAGLE fastIBD 允许以中等计算强度识别大量不相关群体中的罕见变异。即使随着全基因组测序的发展，IBD 作图仍然可能是缩小优先测序感兴趣区域的一种有前途的方法。
Genome-wide association studies (GWAS) have identified around 60 common variants associated with multiple sclerosis (MS), but these loci only explain a fraction of the heritability of MS. Some missing heritability may be caused by rare variants that have been suggested to play an important role in the aetiology of complex diseases such as MS. However current genetic and statistical methods for detecting rare variants are expensive and time consuming. ‘Population-based linkage analysis’ (PBLA) or so called identity-by-descent (IBD) mapping is a novel way to detect rare variants in extant GWAS datasets. We employed BEAGLE fastIBD to search for rare MS variants utilising IBD mapping in a large GWAS dataset of 3,543 cases and 5,898 controls. We identified a genome-wide significant linkage signal on chromosome 19 (LOD = 4.65; p = 1.9×10−6). Network analysis of cases and controls sharing haplotypes on chromosome 19 further strengthened the association as there are more large networks of cases sharing haplotypes than controls. This linkage region includes a cluster of zinc finger genes of unknown function. Analysis of genome wide transcriptome data suggests that genes in this zinc finger cluster may be involved in very early developmental regulation of the CNS. Our study also indicates that BEAGLE fastIBD allowed identification of rare variants in large unrelated population with moderate computational intensity. Even with the development of whole-genome sequencing, IBD mapping still may be a promising way to narrow down the region of interest for sequencing priority.
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影响因子：
3.7
作者：
Fathi A;Hatami M;Hajihosseini V;Fattahi F;Kiani S;Baharvand H;Salekdeh GH
通讯作者：
Salekdeh GH
DOI：
10.1038/ejhg.2009.41
发表时间：
2009-10
期刊：
European journal of human genetics : EJHG
影响因子：
--
作者：
通讯作者：
--
影响因子：
7
作者：
Gusev, Alexander;Lowe, Jennifer K.;Pe'er, Itsik
通讯作者：
Pe'er, Itsik
影响因子：
14.9
作者：
Barrett T;Troup DB;Wilhite SE;Ledoux P;Evangelista C;Kim IF;Tomashevsky M;Marshall KA;Phillippy KH;Sherman PM;Muertter RN;Holko M;Ayanbule O;Yefanov A;Soboleva A
通讯作者：
Soboleva A
影响因子：
5.8
作者：
Hansen, T;Skytthe, A;Kyvik, KO
通讯作者：
Kyvik, KO