2012年10月8日 訊 /生物谷BIOON/ --刊登在國際雜志PLoS One上的一篇研究報(bào)告中，來自波士頓大學(xué)醫(yī)學(xué)院（BUSM）的研究者首次進(jìn)行了帕金森疾?。≒D）相關(guān)遺傳突變的全基因組評(píng)估分析研究,，同時(shí)研究者揭示了PD風(fēng)險(xiǎn)的特定遺傳基因。
在文章中,，研究者發(fā)現(xiàn)基因SNCA,， MAPT， GAK/DGKQ,， HLA和RIT2或其附近的遺傳突變都可以使得PD發(fā)病風(fēng)險(xiǎn)增加,，但是其背后的機(jī)制并不清楚,。其中一種可能性就是突變可以改變大腦基因的表達(dá)方式,，從而使得發(fā)病風(fēng)險(xiǎn)增加,。
研究者檢測(cè)了26個(gè)PD患者以及24個(gè)健康個(gè)體，對(duì)其PD相關(guān)的遺傳突變和大腦基因的表達(dá)水平進(jìn)行了分析,，和突變位置非?？拷倪z傳突變效應(yīng)稱為cis效應(yīng)，距離突變較遠(yuǎn)的基因突變效應(yīng)稱為trans效應(yīng),。
cis效應(yīng)分析揭示了MAPT區(qū)域的遺傳突變和多重的相近的基因的表達(dá)直接相關(guān),，包括基因LOC644246、LRRC37A,、LRRC37A2和DCAKD，在6號(hào)染色體HLA區(qū)域和相近基因HLA-DQA1之間的cis效應(yīng)也比較明顯,。而trans效應(yīng)揭示了23個(gè)DNA序列的突變,，包括SNCA、MAPT及RIT2的基因的突變,。
研究者M(jìn)yers表示,，PD疾病特異性突變基因多的識(shí)別為更深入理解PD模型以及特定藥物開發(fā)靶點(diǎn)，提供了新的思路。（生物谷Bioon.com）
編譯自：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.
