Baranzini Sergio E, Wang Joanne, Gibson Rachel A, Galwey Nicholas, Naegelin Yvonne, Barkhof Frederik, Radue Ernst-Wilhelm, Lindberg Raija L P, Uitdehaag Bernard M G, Johnson Michael R, Angelakopoulou Aspasia, Hall Leslie, Richardson Jill C, Prinjha Rab K, Gass Achim, Geurts Jeroen J G, Kragt Jolijn, Sombekke Madeleine, Vrenken Hugo, Qualley Pamela, Lincoln Robin R, Gomez Refujia, Caillier Stacy J, George Michaela F, Mousavi Hourieh, Guerrero Rosa, Okuda Darin T, Cree Bruce A C, Green Ari J, Waubant Emmanuelle, Goodin Douglas S, Pelletier Daniel, Matthews Paul M, Hauser Stephen L, Kappos Ludwig, Polman Chris H, Oksenberg Jorge R
Department of Neurology, University of California, San Francisco, CA 94143-0435, USA.
Hum Mol Genet. 2009 Feb 15;18(4):767-78. doi: 10.1093/hmg/ddn388. Epub 2008 Nov 14.
Multiple sclerosis (MS), a chronic disorder of the central nervous system and common cause of neurological disability in young adults, is characterized by moderate but complex risk heritability. Here we report the results of a genome-wide association study performed in a 1000 prospective case series of well-characterized individuals with MS and group-matched controls using the Sentrix HumanHap550 BeadChip platform from Illumina. After stringent quality control data filtering, we compared allele frequencies for 551 642 SNPs in 978 cases and 883 controls and assessed genotypic influences on susceptibility, age of onset, disease severity, as well as brain lesion load and normalized brain volume from magnetic resonance imaging exams. A multi-analytical strategy identified 242 susceptibility SNPs exceeding established thresholds of significance, including 65 within the MHC locus in chromosome 6p21.3. Independent replication confirms a role for GPC5, a heparan sulfate proteoglycan, in disease risk. Gene ontology-based analysis shows a functional dichotomy between genes involved in the susceptibility pathway and those affecting the clinical phenotype.
多发性硬化症（MS）是一种中枢神经系统的慢性疾病，也是年轻人神经功能障碍的常见原因，其特征是具有中等程度但复杂的风险遗传度。在此，我们报告了一项全基因组关联研究的结果，该研究使用Illumina公司的Sentrix HumanHap550 BeadChip平台，对1000例特征明确的MS患者前瞻性病例系列以及与之匹配的对照组进行了研究。经过严格的质量控制数据筛选后，我们比较了978例患者和883例对照中551642个单核苷酸多态性（SNP）的等位基因频率，并评估了基因型对易感性、发病年龄、疾病严重程度以及磁共振成像检查中的脑病变负荷和标准化脑容量的影响。一种多分析策略确定了242个超过既定显著性阈值的易感SNP，其中包括位于6号染色体p21.3区域主要组织相容性复合体（MHC）基因座内的65个SNP。独立重复验证表明，硫酸乙酰肝素蛋白聚糖GPC5在疾病风险中发挥作用。基于基因本体论的分析显示，参与易感性途径的基因与影响临床表型的基因之间存在功能二分法。
