Genome-wide association study of severity in multiple sclerosis.
Genome-wide association study of severity in multiple sclerosis.
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DOI：
10.1038/gene.2011.34
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发表时间：
2011-12
影响因子：
5
通讯作者：
International Multiple Sclerosis Genetics Consortium
中科院分区：
文献类型：
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作者：
International Multiple Sclerosis Genetics Consortium
多发性硬化症 (MS) 是一种中枢神经系统慢性炎症性疾病，具有很强的遗传因素。多项证据支持遗传因素在影响多发性硬化症疾病易感性和临床结果方面发挥着重要作用。识别区分特定疾病亚组和/或预测严重临床结果的遗传变异对于进一步了解疾病机制和指导有效治疗方法的开发至关重要。我们研究了 1470 例多发性硬化症病例，并对超过 250 万个单核苷酸多态性进行了全基因组关联研究，以确定影响疾病严重程度的位点，并使用多发性硬化症严重程度评分 (MSSS)（一种临床残疾衡量标准）进行测量。值得注意的是，没有任何一项结果具有全基因组意义。此外，先前确认的多发性硬化症易感位点内的变异似乎不会影响严重程度。尽管生物信息学分析强调了我们结果中过度代表的某些途径，但我们得出的结论是，疾病严重程度的遗传结构可能是多基因的，并且由适度的影响组成，类似于迄今为止对多发性硬化症易感性的描述。然而，不能排除罕见变异的重大影响。重要的是，我们的结果还表明，当将 MSSS 视为二元或连续表型变量时，相比之下，MSSS 是一个稳定的结果。
Multiple sclerosis (MS) is a chronic inflammatory disorder of the central nervous system with a strong genetic component. Several lines of evidence support a strong role for genetic factors influencing both disease susceptibility and clinical outcome in MS. Identification of genetic variants that distinguish particular disease subgroups and/or predict a severe clinical outcome is critical to further our understanding of disease mechanisms and guide development of effective therapeutic approaches. We studied 1470 MS cases and performed a genome-wide association study of more than 2.5 million single-nucleotide polymorphisms to identify loci influencing disease severity, measured using the MS severity score (MSSS), a measure of clinical disability. Of note, no single result achieved genome-wide significance. Furthermore, variants within previously confirmed MS susceptibility loci do not appear to influence severity. Although bioinformatic analyses highlight certain pathways that are over-represented in our results, we conclude that the genetic architecture of disease severity is likely polygenic and comprised of modest effects, similar to what has been described for MS susceptibility, to date. However, a role for major effects of rare variants cannot be excluded. Importantly, our results also show the MSSS, when considered as a binary or continuous phenotype variable is by comparison a stable outcome.