Dyment David A, Sadovnick A Dessa, Willer Cristen J, Armstrong Holly, Cader Zameel M, Wiltshire Steven, Kalman Bernadette, Risch Neil, Ebers George C
The Wellcome Trust Center for Human Genetics, Oxford, UK.
Hum Mol Genet. 2004 May 15;13(10):1005-15. doi: 10.1093/hmg/ddh123. Epub 2004 Apr 6.
Multiple sclerosis (MS) is a complex trait with a sibling relative risk (lambda(sibs)) between 18 and 36. We report a multistage genome scan of 552 sibling pairs from 442 families, the largest MS family sample assessed for linkage. The first stage consisted of a genome scan for linkage with 498 microsatellite markers at an average spacing of 7 cM in 219 sibling pairs. The second stage involved further genotyping of markers from positive regions in an independent sample of 333 affected sibling pairs. The global distribution of allele sharing for all markers showed a shift towards greater sharing within the affected sibling pair group but not in the discordant sibling pair group. This shift indicates that the number of contributing genetic factors is likely to be moderate to large. Only markers at chromosome 6p showed significant evidence for linkage (MLOD=4.40), while other regions were only suggestive (1p, 2q, 5p, 9q, 11p, 12q, 18p, 18q and 21q) with MLODs greater than 1.0. The replication analysis involving all 552 affected sibling pairs confirmed suggestive evidence for five locations, namely, 2q27 (MLOD=2.27), 5p15 (MLOD=2.09), 18p11 (MLOD=1.68), 9q21 (MLOD=1.58) and 1p31 (MLOD=1.33). Suggestive linkage evidence for a previously reported location on chromosome 17q (MLOD=1.67) and a prior association with marker D17S789 was replicated. We showed that the overall excess allele sharing we observed for the entire sample was due to increased allele sharing within the DRB1*15 negative subgroup alone. This observation is most consistent with a model of genetic heterogeneity between HLA and other genetic loci. These findings offer guidance for future genetic studies including dense SNP linkage disequilibrium analysis.
多发性硬化症（MS）是一种复杂性状，其同胞相对风险（lambda(sibs)）在18至36之间。我们报告了对来自442个家庭的552对同胞进行的多阶段基因组扫描，这是评估连锁关系的最大的MS家庭样本。第一阶段包括在219对同胞中对498个微卫星标记进行连锁基因组扫描，平均间距为7厘摩。第二阶段涉及在333对受影响同胞的独立样本中对来自阳性区域的标记进行进一步基因分型。所有标记的等位基因共享的全局分布显示，在受影响同胞对组内共享增加，但在不一致同胞对组中没有。这种变化表明，起作用的遗传因素数量可能为中等至大量。只有6号染色体p臂上的标记显示出显著的连锁证据（最大优势对数 = 4.40），而其他区域只有提示性证据（1号染色体p臂、2号染色体q臂、5号染色体p臂、9号染色体q臂、11号染色体p臂、12号染色体q臂、18号染色体p臂、18号染色体q臂和21号染色体q臂），最大优势对数大于1.0。涉及所有552对受影响同胞的重复分析证实了五个位置的提示性证据，即2q27（最大优势对数 = 2.27）、5p15（最大优势对数 = 2.09）、18p11（最大优势对数 = 1.68）、9q21（最大优势对数 = 1.58）和1p31（最大优势对数 = 1.33）。先前报道的17号染色体q臂上一个位置的提示性连锁证据（最大优势对数 = 1.67）以及与标记D17S789的先前关联得到了重复验证。我们表明，我们在整个样本中观察到的总体等位基因共享过量仅归因于DRB1*15阴性亚组内等位基因共享的增加。这一观察结果与HLA和其他基因座之间的遗传异质性模型最为一致。这些发现为未来的遗传研究提供了指导，包括密集单核苷酸多态性连锁不平衡分析。
