Increased brain expression of GPNMB is associated with genome wide significant risk for Parkinson's disease on chromosome 7p15.3.
Increased brain expression of GPNMB is associated with genome wide significant risk for Parkinson's disease on chromosome 7p15.3.
复制标题
DOI：
10.1007/s10048-017-0514-8
复制
发表时间：
2017-07
期刊：
影响因子：
2.2
通讯作者：
Trabzuni D
中科院分区：
文献类型：
--
作者：
Murthy MN;Blauwendraat C;UKBEC;Guelfi S;IPDGC;Hardy J;Lewis PA;Trabzuni D
帕金森病（PD）的全基因组关联研究（GWAS）先前已经揭示了与染色体7p15.3上的位点的显著关联，该位点最初被指定为糖蛋白非转移性黑素瘤蛋白B（GPNMB）位点。在这项研究中，通过整合不同的表达数量性状基因座（eQTL）数据集（Braineac，CAGEseq，GTEx和表型-基因型整合器（PheGenI）），深入探讨了这种关联对表达的功能影响。最高风险SNP rs 199347 eQTL显示GPNMB、KLHL 7和NUPL 2的表达增加，其中主要等位基因（AA）在脑中，最显著的eQTL在皮质区域，其次是壳核。此外，在GTEx中观察到反义RNA KLHL 7-AS 1的表达降低。此外，rs 199347是一个具有长非编码RNA的eQTL（AC005082.12），在人类组织中除了脑之外。有趣的是，NUPL 2和KLHL 7-AS 1在免疫相关组织（脾和淋巴母细胞）中观察到转录特异性eQTL，这表明该eQTL在特定组织，特定时间点的细胞类型中具有复杂的功能作用。与rs 199347连锁的GPNMB的显著增加的表达在所有数据集中是一致的，并且与位于GPNMB基因内的风险SNP组合，这些结果表明GPNMB的表达增加是解释该基因座与PD关联的因果联系。然而，不能排除其他转录本eQTL和随后的功能作用。这突出了进一步研究的重要性，以了解编码基因，反义和非编码RNA物质之间的功能相互作用，考虑组织和细胞类型特异性，以了解PD的潜在生物学机制。本文的在线版本（doi：10.1007/s10048-017-0514-8）包含补充材料，可供授权用户使用。
Genome wide association studies (GWAS) for Parkinson’s disease (PD) have previously revealed a significant association with a locus on chromosome 7p15.3, initially designated as the glycoprotein non-metastatic melanoma protein B (GPNMB) locus. In this study, the functional consequences of this association on expression were explored in depth by integrating different expression quantitative trait locus (eQTL) datasets (Braineac, CAGEseq, GTEx, and Phenotype-Genotype Integrator (PheGenI)). Top risk SNP rs199347 eQTLs demonstrated increased expressions of GPNMB, KLHL7, and NUPL2 with the major allele (AA) in brain, with most significant eQTLs in cortical regions, followed by putamen. In addition, decreased expression of the antisense RNA KLHL7-AS1 was observed in GTEx. Furthermore, rs199347 is an eQTL with long non-coding RNA (AC005082.12) in human tissues other than brain. Interestingly, transcript-specific eQTLs in immune-related tissues (spleen and lymphoblastoid cells) for NUPL2 and KLHL7-AS1 were observed, which suggests a complex functional role of this eQTL in specific tissues, cell types at specific time points. Significantly increased expression of GPNMB linked to rs199347 was consistent across all datasets, and taken in combination with the risk SNP being located within the GPNMB gene, these results suggest that increased expression of GPNMB is the causative link explaining the association of this locus with PD. However, other transcript eQTLs and subsequent functional roles cannot be excluded. This highlights the importance of further investigations to understand the functional interactions between the coding genes, antisense, and non-coding RNA species considering the tissue and cell-type specificity to understand the underlying biological mechanisms in PD. The online version of this article (doi:10.1007/s10048-017-0514-8) contains supplementary material, which is available to authorized users.
登录
查看更多内容
影响因子：
3.7
作者：
Marques AR;Gabriel TL;Aten J;van Roomen CP;Ottenhoff R;Claessen N;Alfonso P;Irún P;Giraldo P;Aerts JM;van Eijk M
通讯作者：
van Eijk M
剪接的组织特异性遗传控制：对复杂性状的研究的影响。
影响因子：
9.8
作者：
Heinzen EL;Ge D;Cronin KD;Maia JM;Shianna KV;Gabriel WN;Welsh-Bohmer KA;Hulette CM;Denny TN;Goldstein DB
通讯作者：
Goldstein DB
影响因子：
16.6
作者：
Thibodeau SN;French AJ;McDonnell SK;Cheville J;Middha S;Tillmans L;Riska S;Baheti S;Larson MC;Fogarty Z;Zhang Y;Larson N;Nair A;O'Brien D;Wang L;Schaid DJ
通讯作者：
Schaid DJ
影响因子：
9.8
作者：
Schadt EE;Molony C;Chudin E;Hao K;Yang X;Lum PY;Kasarskis A;Zhang B;Wang S;Suver C;Zhu J;Millstein J;Sieberts S;Lamb J;GuhaThakurta D;Derry J;Storey JD;Avila-Campillo I;Kruger MJ;Johnson JM;Rohl CA;van Nas A;Mehrabian M;Drake TA;Lusis AJ;Smith RC;Guengerich FP;Strom SC;Schuetz E;Rushmore TH;Ulrich R
通讯作者：
Ulrich R
影响因子：
25
作者：
Ramasamy, Adaikalavan;Trabzuni, Daniah;Guelfi, Sebastian;Varghese, Vibin;Smith, Colin;Walker, Robert;De, Tisham;Coin, Lachlan;de Silva, Rohan;Cookson, Mark R.;Singleton, Andrew B.;Hardy, John;Ryten, Mina;Weale, Michael E.
通讯作者：
Weale, Michael E.