Gene linkage study of multiple sclerosis sibling pairs

 描述（由申请人提供）：全基因组关联研究通过鉴定110种非HLA遗传关联和解构MHC基因组对疾病风险的影响，极大地促进了对多发性硬化（MS）发病机制的理解。在绘制这种慢性、使人衰弱的中枢神经系统疾病的额外风险基因方面的进展可能是立即的。然而，迄今为止，所有大型遗传学研究都集中在MS的易感性，而不是临床表达或病程;进展的遗传因素仍有待揭示。我们假设等位基因易感性变体在赋予表型累积生理效应的功能网络内起作用，并且不同功能通路内的遗传负担将在与神经元损伤和随后的残疾相关的MRI指标中机械地反映。我们提出了两个主要的研究目标，桥接假设驱动的遗传实验与神经元损失的可测量指标，以确定临床进展的遗传基础。具体目标1描述了全球遗传负担评分统计的发展和经验验证，该统计将患者分层的机械注释纳入功能性疾病 根据每个个体携带的遗传风险变体的本体论富集来划分亚型。特定目标2利用新型高场MRI序列来描述有限数量的相关定量MRI表型，反映了进展生物学的特定方面，即大脑和脊髓的灰质和白色体积。尽管该提案依赖于各种雄心勃勃且具有挑战性的方法和分析方法，但重要的是要强调我们在MS的临床，成像和实验室方面以及数据管理，生物信息学和统计分析方面拥有丰富的经验。一个已知的基因或一组基因对MS过程的即使是适度的功能作用的证明，也可以帮助阐明基本的疾病机制，并产生一个重要的治疗机会。同样令人兴奋的是，有可能更好地了解疾病的异质性，并根据基因型评分、分子途径和与其他疾病的遗传学共享进行合理的重新分类。

 DESCRIPTION (provided by applicant): Genome wide association studies have contributed greatly to the understanding of multiple sclerosis (MS) pathogenesis through the identification of 110 non-HLA genetic associations and deconstruction of the MHC genomic effects on disease risk. Progress in mapping additional risk-genes for this chronic, debilitating disease of the central nervous system is likely to be immediate. However, all large genetic studies to date have focused on susceptibility and not clinical expression or course of MS; genetic contributors to progression remain to be revealed. We hypothesize that allelic susceptibility variants act within functional networks that confer cumulative physiological effects on the phenotype, and that genetic burdens within distinct functional pathways will be reflected mechanistically in MRI metrics associates with neuronal damage and consequent disability. We propose two main research goals, bridging hypothesis driven genetic experiments with measurable indicators of neuronal loss to identify the genetic underpinnings of clinical progression. Specific Aim 1 describes the development and empirical validation of global genetic burden scoring statistics that incorporate mechanistic annotations for the stratification of patients into functional disease sub-types according to the ontological enrichment of the genetic risk variants each individual carries. Specific Aim 2 takes advantage of novel high-field MRI sequences to describe a limited number of correlated quantitative MRI phenotypes reflecting a specific aspect of the biology of progression, namely grey and white matter volumes of the brain and spinal cord. Although this proposal relies on a variety of ambitious and challenging methodological and analytical approaches, it is important to emphasize that we have extensive experience in clinical, imaging, and laboratory aspects of MS, together with data management, bio-informatics, and statistical analysis. The demonstration of even a modest functional effect of a known gene or group of genes on the course of MS could help elucidate fundamental disease mechanisms and yield a major therapeutic opportunity. Equally exciting is the potential for a better understanding of disease heterogeneity and rational reclassification on the basis of genotype scores, molecular pathways, and shared genetics with other diseases.