An integrative transethnic approach to identify novel functional genes in Parkinson's disease using in silico and in vivo experiments

使用计算机和体内实验识别帕金森病新功能基因的综合跨种族方法

• 批准号: MR/X011070/1
• 负责人: Nikolas Maniatis
• 金额: $ 137.33万
• 依托单位: University College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FX011070%2F1
• 关键词: integrative; transethnic; approach; identify; novel

Interpretation of GWAS results for PD have to date been very challenging. It is now well established that the vast majority of variants with a functional role in PD and other complex diseases are likely to be non-coding and regulatory. As a result, the actual implicated functional genes remain largely undefined. This study encompasses both in silico and in vivo experiments with the aim of dissecting the genetic aetiology of PD. With regards to in silico analyses, our research group has made important progress in this field by using genetic maps to effectively integrate high-resolution in silico data at disease loci to infer function. The multi-marker mapping method we use obtains replicated estimates for precise causal locations based on population-specific genetic maps that have distances expressed in additive Linkage Disequilibrium (LD) Units (LDU maps). These maps are constructed for the same population from which the GWAS data was collected. Thus the mapping location analysis takes directly into account the patterns of LD that are specific to that population. Our work demonstrates that replicated disease-associated loci located on LDU maps can be effectively combined with expression data, as well as specific regulatory annotation to help localise the potential functional genetic variants and identify the genes that the loci perturb. Our proposal is to apply the same computational methods to the analysis of genomic and transcriptomic data to advance the identification of the functionally implicated genes and pathways related to PD. The most promising disease transethnic loci and corresponding implicated functional genes will be screened and validated using two well-established Drosophila models of PD. Our proposal provides the unique opportunity to use both in silico mapping and follow up with in vivo functional experiments in order to obtain greater insights into the genetics of PD. The identification and functional elucidation of PD susceptibility genes holds great promise for the discovery of new therapeutic targets and treatment strategies in PD.

迄今为止，对PD的GWAS结果的解释非常具有挑战性。现在已经确定，在PD和其他复杂疾病中具有功能作用的绝大多数变异可能是非编码和调控的。因此，实际涉及的功能基因在很大程度上仍未确定。本研究包括计算机和体内实验，目的是解剖PD的遗传病因。在计算机分析方面，我们课题组利用遗传图谱有效整合疾病位点的高分辨率计算机数据推断功能，在该领域取得了重要进展。我们使用的多标记作图方法获得了精确因果位置的复制估计，该方法基于群体特异性遗传图，这些遗传图的距离在加性连锁不平衡（LD）单元（LDU图）中表示。这些地图是为收集GWAS数据的同一人口构建的。因此，映射位置分析直接考虑了特定于该种群的LD模式。我们的工作表明，位于LDU地图上的复制疾病相关基因座可以有效地与表达数据以及特定的调控注释相结合，以帮助定位潜在的功能性遗传变异并识别基因座干扰的基因。我们的建议是应用相同的计算方法来分析基因组和转录组数据，以推进与PD相关的功能相关基因和途径的鉴定。最有希望的疾病跨民族位点和相应的相关功能基因将通过两种成熟的帕金森病果蝇模型进行筛选和验证。我们的建议提供了一个独特的机会，既可以在芯片上进行定位，也可以在体内进行功能实验，以便更深入地了解PD的遗传学。PD易感基因的鉴定和功能阐明对PD新的治疗靶点和治疗策略的发现具有重要意义。

项目成果

The hazards of genotype imputation when mapping disease susceptibility variants.

• DOI: 10.1186/s13059-023-03140-3
• 发表时间: 2024-01-03
• 期刊: Genome biology
• 影响因子: 12.3