对多巴胺能神经元进行单细胞表达谱分析，并结合关联分析，确定吡哆醛激酶为帕金森病基因。

Single-cell expression profiling of dopaminergic neurons combined with association analysis identifies pyridoxal kinase as Parkinson's disease gene.

机构信息

Institute of Human Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.

出版信息

Ann Neurol. 2009 Dec;66(6):792-8. doi: 10.1002/ana.21780.

DOI:10.1002/ana.21780

PMID:20035503

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC4034432/

Abstract

OBJECTIVE

The etiology of Parkinson disease (PD) is complex and multifactorial, with hereditary and environmental factors contributing. Monogenic forms have provided molecular clues to disease mechanisms but genetic modifiers of idiopathic PD are still to be determined.

METHODS

We carried out whole-genome expression profiling of isolated human substantia nigra (SN) neurons from patients with PD vs. controls followed by association analysis of tagging single-nucleotide polymorphisms (SNPs) in differentially regulated genes. Association was investigated in a German PD sample and confirmed in Italian and British cohorts.

RESULTS

We identified four differentially expressed genes located in PD candidate pathways, ie, MTND2 (mitochondrial, p = 7.14 x 10(-7)), PDXK (vitamin B6/dopamine metabolism, p = 3.27 x 10(-6)), SRGAP3 (axon guidance, p = 5.65 x 10(-6)), and TRAPPC4 (vesicle transport, p = 5.81 x 10(-6)). We identified a DNA variant (rs2010795) in PDXK associated with an increased risk of PD in the German cohort (p = 0.00032). This association was confirmed in the British (p = 0.028) and Italian (p = 0.0025) cohorts individually and reached a combined value of p = 1.2 x 10(-7) (odds ratio [OR], 1.3; 95% confidence interval [CI], 1.18-1.44).

INTERPRETATION

We provide an example of how microgenomic genome-wide expression studies in combination with association analysis can aid to identify genetic modifiers in neurodegenerative disorders. The detection of a genetic variant in PDXK, together with evidence accumulating from clinical studies, emphasize the impact of vitamin B6 status and metabolism on disease risk and therapy in PD.

摘要

目的

帕金森病（PD）的病因复杂且具有多因素性，遗传和环境因素都有影响。单基因形式为疾病机制提供了分子线索，但特发性 PD 的遗传修饰因子仍有待确定。

方法

我们对来自 PD 患者和对照者的人 SN 神经元进行了全基因组表达谱分析，然后对差异表达基因的标记单核苷酸多态性（SNP）进行了关联分析。在德国 PD 样本中进行了关联研究，并在意大利和英国队列中进行了验证。

结果

我们确定了四个位于 PD 候选途径中的差异表达基因，即 MTND2（线粒体，p = 7.14 x 10(-7)）、PDXK（维生素 B6/多巴胺代谢，p = 3.27 x 10(-6)）、SRGAP3（轴突导向，p = 5.65 x 10(-6)）和 TRAPPC4（囊泡运输，p = 5.81 x 10(-6)）。我们在 PDXK 中发现了一个与 PD 风险增加相关的 DNA 变异（rs2010795），在德国队列中的 p 值为 0.00032。该关联在英国（p = 0.028）和意大利（p = 0.0025）队列中得到了单独的验证，并达到了联合 p 值为 1.2 x 10(-7)（比值比[OR]，1.3；95%置信区间[CI]，1.18-1.44）。