Yaghoobi Arash, Seyedmirzaei Homa, Ala Moein
Institute for Research in Fundamental Sciences (IPM), School of Biological Sciences, Tehran, Iran.
Interdisciplinary Neuroscience Research Program (INRP), Tehran University of Medical Sciences, Tehran, Iran.
Parkinsons Dis. 2023 Aug 23;2023:2893662. doi: 10.1155/2023/2893662. eCollection 2023.
Despite remarkable progress in identifying Parkinson's disease (PD) genetic risk loci, the genetic basis of PD remains largely unknown. With the help of the endophenotype approach and using data from dopamine transporter single-photon emission computerized tomography (DaTscan), we identified potentially involved genes in PD.
We conducted an imaging genetic study by performing exome-wide association study (EWAS) and genome-wide association study (GWAS) on the specific binding ratio (SBR) of six DaTscan anatomical areas between 489 and 559 subjects of Parkinson's progression markers initiative (PPMI) cohort and 83,623 and 36,845 single-nucleotide polymorphisms (SNPs)/insertion-deletion mutations (INDELs). We also investigated the association of cerebrospinal fluid (CSF) protein concentration of our significant genes with PD progression using PPMI CSF proteome data.
Among 83,623 SNPs/INDELs in EWAS, one SNP (rs201465075) on 1 q32.1 locus was significantly ( value = 4.03 × 10) associated with left caudate DaTscan SBR, and 33 SNPs were suggestive. Among 36,845 SNPs in GWAS, one SNP (rs12450112) on 17 p.12 locus was significantly ( value = 1.34 × 10) associated with right anterior putamen DaTscan SBR, and 39 SNPs were suggestive among which 8 SNPs were intergenic. We found that rs201465075 and rs12450112 are most likely related to and genes. The protein level of in the CSF was significantly associated with PD progression in the PPMI cohort; however, proteomic data were not available for the gene.
We have shown that particular variants of and genes may be associated with PD. Since DaTscan imaging could be positive in other Parkinsonian syndromes, caution should be taken when interpreting our results. Future experimental studies are also needed to verify these findings.
尽管在确定帕金森病（PD）遗传风险位点方面取得了显著进展，但PD的遗传基础在很大程度上仍然未知。借助内表型方法并利用多巴胺转运体单光子发射计算机断层扫描（DaTscan）的数据，我们确定了PD中可能涉及的基因。
我们通过对帕金森病进展标志物倡议（PPMI）队列中489至559名受试者以及83,623和36,845个单核苷酸多态性（SNP）/插入缺失突变（INDEL）的六个DaTscan解剖区域的特异性结合率（SBR）进行外显子组全关联研究（EWAS）和全基因组关联研究（GWAS），开展了一项成像遗传学研究。我们还使用PPMI脑脊液蛋白质组数据研究了我们的显著基因的脑脊液（CSF）蛋白浓度与PD进展的关联。
在EWAS的83,623个SNP/INDEL中，1q32.1位点上的一个SNP（rs201465075）与左侧尾状核DaTscan SBR显著相关（P值 = 4.03×10），33个SNP具有提示性。在GWAS的36,845个SNP中，17p.12位点上的一个SNP（rs12450112）与右侧前壳核DaTscan SBR显著相关（P值 = 1.34×10），39个SNP具有提示性，其中8个SNP为基因间区域。我们发现rs201465075和rs12450112最有可能与 和 基因相关。在PPMI队列中，CSF中 的蛋白水平与PD进展显著相关；然而， 基因的蛋白质组数据不可用。
我们已经表明 和 基因的特定变体可能与PD相关。由于DaTscan成像在其他帕金森综合征中可能为阳性，在解释我们的结果时应谨慎。未来还需要进行实验研究来验证这些发现。
