Aggregation of Multiple Sclerosis Genetic Risk Variants in Multiple and Single Case Families
Aggregation of Multiple Sclerosis Genetic Risk Variants in Multiple and Single Case Families
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DOI：
10.1002/ana.22323
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发表时间：
2011-01-01
影响因子：
11.2
通讯作者：
Oksenberg, Jorge R.
中科院分区：
文献类型：
--
作者：
Gourraud, Pierre-Antoine;McElroy, Joseph P.;Oksenberg, Jorge R.
目的：多发性硬化（MS）是一种多因素遗传的神经系统疾病。全基因组关联研究已经在大约16个与易感性相关的基因中鉴定和/或验证了多个多态性。我们的目的是通过比较多个和单一的情况family.Methods：一个加权的对数加性综合方法称为MS遗传负担（MSGB）的遗传MS风险标记在个人的聚集进行调查，以占从以前的关联研究和荟萃分析的完善的遗传变异。结果：MSGB分析显示，多发性MS家系中易感基因的聚集性高于散发性MS家系，多发性MS家系中易感基因的聚集性高于散发性MS家系。此外，非主要组织相容性复合体单核苷酸多态性的聚集既不依赖于性别，也不依赖于HLA-DRB 1 *15：01等位基因的存在或不存在。有趣的是，虽然MS患者的兄弟姐妹中MSGB更大与MS风险增加相关，（优势比，2. 1; p = 0.001），先证者和同胞之间MSGB差异的受试者工作特征曲线（受试者操作曲线下面积，0.57 [95%置信区间，0.53-0.61]）显示MS的病例对照状态预测不能用当前可用的遗传学数据来实现。解释：MSGB概念的主要兴趣在于其将累积遗传贡献整合到MS风险中的能力。该分析强调了已知常见变异的家庭负荷的高度可变性。这种新方法可以扩展到其他遗传复杂疾病。尽管强调组装大型病例对照数据集，多代，多受影响的家庭仍然是一个宝贵的资源，为推进复杂性状的遗传结构的理解。神经网络2011;69：65-74
Objective: Multiple sclerosis (MS) is a multifactorial neurologic disease characterized by modest but tractable heritability. Genome-wide association studies have identified and/or validated multiple polymorphisms in approximately 16 genes associated with susceptibility. We aimed at investigating the aggregation of genetic MS risk markers in individuals by comparing multiple- and single-case families.Methods: A weighted log-additive integrative approach termed MS genetic burden (MSGB) was used to account for the well-established genetic variants from previous association studies and meta-analyses. The corresponding genetic burden and its transmission was analyzed in 1,213 independent MS families (810 sporadic and 403 multicase families).Results: MSGB analysis demonstrated a higher aggregation of susceptibility variants in multicase compared to sporadic MS families. In addition, the aggregation of non-major histocompatibility complex single nucleotide polymorphisms depended neither on gender nor on the presence or absence of HLA-DRB1*15:01 alleles. Interestingly, although a greater MSGB in siblings of MS patients was associated with an increased risk of MS (odds ratio, 2.1; p = 0.001), receiver operating characteristic curves of MSGB differences between probands and sibs (area under the receiver operator curves, 0.57 [95% confidence interval, 0.53-0.61]) show that case-control status prediction of MS cannot be achieved with the currently available genetic data.Interpretation: The primary interest in the MSGB concept resides in its capacity to integrate cumulative genetic contributions to MS risk. This analysis underlines the high variability of family load with known common variants. This novel approach can be extended to other genetically complex diseases. Despite the emphasis on assembling large case-control datasets, multigenerational, multiaffected families remain an invaluable resource for advancing the understanding of the genetic architecture of complex traits. ANN NEUROL 2011;69:65-74