Saarela Janna, Schoenberg Fejzo Marlena, Chen Daniel, Finnilä Saara, Parkkonen Maikki, Kuokkanen Satu, Sobel Eric, Tienari Pentti J, Sumelahti Marja-Liisa, Wikström Juhani, Elovaara Irina, Koivisto Keijo, Pirttilä Tuula, Reunanen Mauri, Palotie Aarno, Peltonen Leena
Department of Human Genetics, UCLA School of Medicine, Los Angeles, CA 90095, USA.
Hum Mol Genet. 2002 Sep 15;11(19):2257-67. doi: 10.1093/hmg/11.19.2257.
Genome-wide linkage analyses performed in a Finnish study sample have identified four potential predisposing loci for multiple sclerosis (MS). Here we made an effort to restrict the wide linkage region on chromosome 17 with a dense set of 31 markers using multipoint linkage analyses and monitoring for shared marker alleles in MS chromosomes. We carried out the linkage analyses in 22 Finnish multiplex MS families originating from a regional subisolate that shows an exceptionally high prevalence of MS in order to minimize the genetic and environmental heterogeneity of the study sample. Thirty markers on the 23 cM initial interval gave positive pairwise LOD scores. We monitored for shared haplotypes among affected family members within a family, and identified an approximately 4 cM region flanked by the markers D17S1792 and ATA43A10 in 17 out of the 22 families (77.3%). The multipoint linkage analyses using Genehunter and SIMWALK 2.40 provided further evidence for the same 4 cM region, for example a maximal multipoint NPL score of 5.98 (P<0.0002). We observed nominal evidence for association to MS, with one marker flanking the shared region, and this association was replicated in the additional set of families. Using the combined power of linkage, association and shared haplotype analyses, we were thus able to restrict the MS locus on chromosome 17q from 23 cM to a 4 cM region covering a physical interval of approximately 2.5 Mb. Thus, this study describes the restriction of an MS locus outside the HLA region into a segment approachable by molecular tools.
在芬兰研究样本中进行的全基因组连锁分析已经确定了多发性硬化症（MS）的四个潜在易感基因座。在这里，我们努力使用多点连锁分析和监测MS染色体上共享标记等位基因，用一组密集的31个标记来限制17号染色体上广泛的连锁区域。我们对来自一个区域亚隔离群体的22个芬兰MS家系进行了连锁分析，该群体显示出MS的异常高患病率，以便尽量减少研究样本的遗传和环境异质性。最初23 cM区间上的30个标记给出了正的成对LOD分数。我们监测了一个家系中受影响家庭成员之间的共享单倍型，并在22个家系中的17个（77.3%）中确定了一个大约4 cM的区域，其两侧为标记D17S1792和ATA43A10。使用Genehunter和SIMWALK 2.40进行的多点连锁分析为同一个4 cM区域提供了进一步的证据，例如最大多点NPL分数为5.98（P<0.0002）。我们观察到与MS关联的名义证据，有一个标记位于共享区域的一侧，并且这种关联在另外一组家系中得到了重复。因此，通过连锁、关联和共享单倍型分析的联合力量，我们能够将17号染色体上的MS基因座从23 cM限制到一个覆盖约2.5 Mb物理区间的4 cM区域。因此，本研究描述了将HLA区域外的一个MS基因座限制到一个可通过分子工具接近的区段。
