2012年10月8日 讯 /生物谷BIOON/ --刊登在国际杂志PLoS One上的一篇研究报告中，来自波士顿大学医学院（BUSM）的研究者首次进行了帕金森疾病（PD）相关遗传突变的全基因组评估分析研究，同时研究者揭示了PD风险的特定遗传基因。
在文章中，研究者发现基因SNCA， MAPT， GAK/DGKQ， HLA和RIT2或其附近的遗传突变都可以使得PD发病风险增加，但是其背后的机制并不清楚。其中一种可能性就是突变可以改变大脑基因的表达方式，从而使得发病风险增加。
研究者检测了26个PD患者以及24个健康个体，对其PD相关的遗传突变和大脑基因的表达水平进行了分析，和突变位置非常靠近的遗传突变效应称为cis效应，距离突变较远的基因突变效应称为trans效应。
cis效应分析揭示了MAPT区域的遗传突变和多重的相近的基因的表达直接相关，包括基因LOC644246、LRRC37A、LRRC37A2和DCAKD，在6号染色体HLA区域和相近基因HLA-DQA1之间的cis效应也比较明显。而trans效应揭示了23个DNA序列的突变，包括SNCA、MAPT及RIT2的基因的突变。
研究者Myers表示，PD疾病特异性突变基因多的识别为更深入理解PD模型以及特定药物开发靶点，提供了新的思路。（生物谷Bioon.com）
编译自：Genetic Variants' Role in Increasing Parkinson's Disease Risk Investigated
doi:10.1371/journal.pone.0046199
PMC:
PMID:
Evaluation of Parkinson Disease Risk Variants as Expression-QTLs
Jeanne C. Latourelle1*, Alexandra Dumitriu1,2, Tiffany C. Hadzi1, Thomas G. Beach3, Richard H. Myers1,2
The recent Parkinson Disease GWAS Consortium meta-analysis and replication study reports association at several previously confirmed risk loci SNCA, MAPT, GAK/DGKQ, and HLA and identified a novel risk locus at RIT2. To further explore functional consequences of these associations, we investigated modification of gene expression in prefrontal cortex brain samples of pathologically confirmed PD cases (N = 26) and controls (N = 24) by 67 associated SNPs in these 5 loci. Association between the eSNPs and expression was evaluated using a 2-degrees of freedom test of both association and difference in association between cases and controls, adjusted for relevant covariates. SNPs at each of the 5 loci were tested for cis-acting effects on all probes within 250 kb of each locus. Trans-effects of the SNPs on the 39,122 probes passing all QC on the microarray were also examined. From the analysis of cis-acting SNP effects, several SNPs in the MAPT region show significant association to multiple nearby probes, including two strongly correlated probes targeting the gene LOC644246 and the duplicated genes LRRC37A and LRRC37A2, and a third uncorrelated probe targeting the gene DCAKD. Significant cis-associations were also observed between SNPs and two probes targeting genes in the HLA region on chromosome 6. Expanding the association study to examine trans effects revealed an additional 23 SNP-probe associations reaching statistical significance (p<2.8×10−8) including SNPs from the SNCA, MAPT and RIT2 regions. These findings provide additional context for the interpretation of PD associated SNPs identified in recent GWAS as well as potential insight into the mechanisms underlying the observed SNP associations.
