Middleton F A, Pato M T, Gentile K L, Morley C P, Zhao X, Eisener A F, Brown A, Petryshen T L, Kirby A N, Medeiros H, Carvalho C, Macedo A, Dourado A, Coelho I, Valente J, Soares M J, Ferreira C P, Lei M, Azevedo M H, Kennedy J L, Daly M J, Sklar P, Pato C N
Department of Neuroscience and Physiology, State University of New York (SUNY), Syracuse, NY, USA.
Am J Hum Genet. 2004 May;74(5):886-97. doi: 10.1086/420775. Epub 2004 Apr 1.
We performed a linkage analysis on 25 extended multiplex Portuguese families segregating for bipolar disorder, by use of a high-density single-nucleotide-polymorphism (SNP) genotyping assay, the GeneChip Human Mapping 10K Array (HMA10K). Of these families, 12 were used for a direct comparison of the HMA10K with the traditional 10-cM microsatellite marker set and the more dense 4-cM marker set. This comparative analysis indicated the presence of significant linkage peaks in the SNP assay in chromosomal regions characterized by poor coverage and low information content on the microsatellite assays. The HMA10K provided consistently high information and enhanced coverage throughout these regions. Across the entire genome, the HMA10K had an average information content of 0.842 with 0.21-Mb intermarker spacing. In the 12-family set, the HMA10K-based analysis detected two chromosomal regions with genomewide significant linkage on chromosomes 6q22 and 11p11; both regions had failed to meet this strict threshold with the microsatellite assays. The full 25-family collection further strengthened the findings on chromosome 6q22, achieving genomewide significance with a maximum nonparametric linkage (NPL) score of 4.20 and a maximum LOD score of 3.56 at position 125.8 Mb. In addition to this highly significant finding, several other regions of suggestive linkage have also been identified in the 25-family data set, including two regions on chromosome 2 (57 Mb, NPL = 2.98; 145 Mb, NPL = 3.09), as well as regions on chromosomes 4 (91 Mb, NPL = 2.97), 16 (20 Mb, NPL = 2.89), and 20 (60 Mb, NPL = 2.99). We conclude that at least some of the linkage peaks we have identified may have been largely undetected in previous whole-genome scans for bipolar disorder because of insufficient coverage or information content, particularly on chromosomes 6q22 and 11p11.
我们使用高密度单核苷酸多态性（SNP）基因分型检测方法——基因芯片人类图谱10K阵列（HMA10K），对25个葡萄牙扩展性双相情感障碍家系进行了连锁分析。在这些家系中，12个家系用于HMA10K与传统的10厘摩（cM）微卫星标记集以及密度更高的4厘摩标记集的直接比较。这项比较分析表明，在微卫星检测中覆盖度差且信息含量低的染色体区域，SNP检测中存在显著的连锁峰。HMA10K在这些区域始终提供高信息含量并增强了覆盖度。在整个基因组中，HMA10K的平均信息含量为0.842，标记间距为0.21兆碱基（Mb）。在这12个家系组中，基于HMA10K的分析在6号染色体q22和11号染色体p11上检测到两个全基因组显著连锁的染色体区域；在微卫星检测中，这两个区域均未达到这一严格阈值。完整的25个家系集合进一步强化了6号染色体q22上的研究结果，在125.8兆碱基处达到全基因组显著性，最大非参数连锁（NPL）得分为4.20，最大对数优势（LOD）得分为3.56。除了这一高度显著的发现外，在25个家系数据集中还鉴定出了其他几个提示性连锁区域，包括2号染色体上的两个区域（57兆碱基，NPL = 2.98；145兆碱基，NPL = 3.09），以及4号（91兆碱基，NPL = 2.97）、16号（20兆碱基，NPL = 2.89）和20号（60兆碱基，NPL = 2.99）染色体上的区域。我们得出结论，由于覆盖度或信息含量不足，尤其是在6号染色体q22和11号染色体p11上，我们所鉴定出的至少一些连锁峰在先前双相情感障碍的全基因组扫描中可能基本未被检测到。
