Integration of transcriptome-wide association study with neuronal dysfunction assays provides functional genomics evidence for Parkinson's disease genes.
Integration of transcriptome-wide association study with neuronal dysfunction assays provides functional genomics evidence for Parkinson's disease genes.
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全转录组关联研究与神经元功能障碍测定的整合为帕金森病基因提供了功能基因组学证据。
DOI：
10.1093/hmg/ddac230
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发表时间：
2023
影响因子：
3.5
通讯作者：
Botas,Juan
中科院分区：
文献类型：
--
作者：
Li,Jiayang;Amoh,BismarkKojo;McCormick,Emma;Tarkunde,Akash;Zhu,KatyFan;Perez,Alma;Mair,Megan;Moore,Justin;Shulman,JoshuaM;Al-Ramahi,Ismael;Botas,Juan
全基因组关联研究（GWAS）已经显著提高了我们对帕金森病（PD）遗传学的理解，但目前它们并不能解释PD的完全遗传性。在许多情况下，由于GWAS不能提供已鉴定候选基因座的功能信息，因此很难明确地鉴定每个基因座内的特定基因。在这里，我们提出了一个综合的方法，结合转录组关联研究（TWAS）和高通量的神经元功能障碍分析在果蝇中发现和验证候选PD基因。我们通过TWAS确定了160个候选基因，其错误表达与PD风险相关。使用正交硅方法对候选物进行验证，发现其在功能上与PD相关途径（即内溶酶体）相关。然后，我们在果蝇PD模型中模拟这些TWAS预测的转录组学改变，发现50个候选基因可以调节α-突触核蛋白（α-Syn）诱导的神经变性，使我们能够在先前已知的PD基因座中提名新基因。我们还发现了GWAS突变体中其他新的PD候选基因（例如TTC 19、ADORA 2B、LZTS 3、NRBP 1、HN 1 L），这些基因也得到了临床和功能证据的支持。这些发现加深了我们对PD的理解，并支持将我们的综合方法应用于其他复杂的特质障碍。
Genome-wide association studies (GWAS) have markedly advanced our understanding of the genetics of Parkinson’s disease (PD), but they currently do not account for the full heritability of PD. In many cases it is difficult to unambiguously identify a specific gene within eachlocusbecause GWAS does not provide functional information on the identified candidateloci. Here we present an integrative approach that combines transcriptome-wide association study (TWAS) with high-throughput neuronal dysfunction analyses inDrosophilato discover and validate candidate PD genes. We identified 160 candidate genes whose misexpression is associated with PD risk via TWAS. Candidates were validated using orthogonalin silicomethods and found to be functionally related to PD-associated pathways (i.e. endolysosome). We then mimicked these TWAS-predicted transcriptomic alterations in aDrosophilaPD model and discovered that 50 candidates can modulate α-Synuclein(α-Syn)-induced neurodegeneration, allowing us to nominate new genes in previously known PD loci. We also uncovered additional novel PD candidate genes within GWAS suggestiveloci(e.g.TTC19, ADORA2B, LZTS3, NRBP1, HN1L), which are also supported by clinical and functional evidence. These findings deepen our understanding of PD, and support applying our integrative approach to other complex trait disorders.