Neurobiology Research Laboratory, Department of Healthcare Biotechnology, Atta-ur-Rahman School of Applied Biosciences, National University of Sciences and Technology, Islamabad, Pakistan.
Neurobiology Research Laboratory, Department of Healthcare Biotechnology, Atta-ur-Rahman School of Applied Biosciences, National University of Sciences and Technology, Islamabad, Pakistan.
Gene. 2018 Sep 25;672:115-125. doi: 10.1016/j.gene.2018.06.011. Epub 2018 Jun 5.
Alzheimer's disease (AD), the most common form of dementia affects 24.3 million people worldwide. More than twenty genetic loci have been associated with AD and a significant number of genetic variants were mapped within these loci. A large proportion of genome wide significant variants lie outside the coding region. However, the plausible function of these variants is still unexplored.
The present study aimed to unravel the regulatory role of proxy single nucleotide polymorphisms (SNPs), to determine their risk of developing AD.
The RegulomeDB was employed to predict the regulatory role of proxy SNPs. Protein association network and functional enrichment analysis was performed using String10.5 and gene ontology, respectively.
A total of 451 SNPs were examined through SNAP web portal (r ≤ 0.80) which returned 2186 proxy SNPs in linkage disequilibrium (LD) with genome wide significant SNPs for AD. Out of 2186 SNPs analyzed in RegulomeDB, 151 had the scores < 3 that indicates the high degree of their potential regulatory function. Further analysis revealed that out of these 151 SNPs, 37 were genome wide significant for AD, 17 were significantly associated with diseases other than AD, 89 were proxy SNPs (not genome wide significant) for various diseases including AD while 8 SNPs were novel proxy SNPs for AD.
These findings support the notion that the non-coding variants can be strongly associated with disease risk. Further validation through genome wide association studies will be helpful for the elucidation of their regulatory potential.
阿尔茨海默病（AD）是最常见的痴呆症形式，影响着全球 2430 万人。有二十多个遗传位点与 AD 相关，其中很大一部分遗传变异都位于这些位点内。大量全基因组显著变异位于编码区之外。然而，这些变异的可能功能仍未被探索。
本研究旨在揭示替代单核苷酸多态性（SNP）的调控作用，以确定其发展为 AD 的风险。
采用 RegulomeDB 预测替代 SNP 的调控作用。使用 String10.5 进行蛋白质关联网络分析，使用基因本体论进行功能富集分析。
通过 SNAP 网络门户（r ≤ 0.80）共检测了 451 个 SNP，其中有 2186 个与 AD 的全基因组显著 SNP 处于连锁不平衡（LD）关系的替代 SNP。在 RegulomeDB 中分析的 2186 个 SNP 中，有 151 个得分<3，表明其潜在调控功能的程度较高。进一步分析显示，在这 151 个 SNP 中，有 37 个与 AD 具有全基因组显著相关性，有 17 个与 AD 以外的疾病显著相关，有 89 个是各种疾病（包括 AD）的替代 SNP（未达到全基因组显著水平），有 8 个 SNP 是 AD 的新型替代 SNP。
这些发现支持了非编码变异与疾病风险密切相关的观点。通过全基因组关联研究进行进一步验证，将有助于阐明其调控潜力。
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