Alpha synuclein (SNCA) rs7684318 variant contributes to Parkinson's disease risk by altering transcription factor binding related with Notch and Wnt signaling

被引：1

作者：

Naushad, Shaik Mohammad ^{[1
]}

Hussain, Tajamul ^{[2
,3
]}

Alrokayan, Salman ^{[3
]}

Kutala, Vijay Kumar ^{[4
]}

机构：

[1] Sandor Special Diagnost Pvt Ltd, Dept Pharmacogen, Banjara Hills,Rd 3, Hyderabad, India

[2] King Saud Univ, Coll Sci, Ctr Excellence Biotechnol Res, Riyadh 11451, Saudi Arabia

[3] King Saud Univ, Coll Sci, Biochem Dept, Riyadh 11451, Saudi Arabia

[4] Nizams Inst Med Sci, Dept Clin Pharmacol & Therapeut, Hyderabad, India

来源：

NEUROSCIENCE LETTERS | 2021年 / 750卷

关键词：

Alpha synuclein; rs7684318; Parkinson's disease; Meta-analysis; DNase footprint analysis; Transcription factor binding; Notch signalling; Wnt-beta catenin signalling;

D O I：

10.1016/j.neulet.2021.135802

中图分类号：

Q189 [神经科学];

学科分类号：

071006 ;

摘要：

In view of inconsistencies in the association studies of alpha synuclein (SNCA) rs7684318 (chr4: 90655003 T > C) with Parkinson's disease (PD), we conducted a meta-analysis to establish the association of this variant with PD and examined changes in transcription factor binding. SNCA rs7684318 C-allele was identified as genetic risk factor for PD in fixed (OR: 1.53, 95 % CI: 1.40-1.68, p < 0.0001) and random effect (OR: 1.65, 95 % CI: 1.30-2.09, p = 0.0003) models. Heterogeneity was observed in association (Tau(2): 0.0576, H: 2.32, I-2: 0.815, Q: 21.64, p = 0.0002). Egger's test showed no evidence of publication bias (p = 0.37). Subgroup analysis showed that rs7684318 is contributing to PD risk in Japanese (OR: 1.46, 95 % CI: 1.30-1.64) and Indian (OR: 2.63, 95 % CI: 1.79-3.86) populations while showing no significant association in Chinese population (OR: 1.68, 95 % CI: 0.93-3.02). Sensitivity analysis showed that exclusion of any one of the studies has no significant impact on the association, which justifies the robustness of the analysis. Tissue-specific DNase foot print analysis revealed that this variant contributes to increased transcription factor binding in midbrain, putamen and caudate nucleus. The substitution of T > C increased binding of RBPJ and GATA-family transcription factors; and decreased binding of NKX2 family, SNAI2, SNAI3, DMRT1, HOXA13, HOXB13, HOXC13, HOXD13, WT1, POU4F1, POU4F2, POU4F3 transcriptional factors. TRANSFAC and DNA curvature analyses substantiate the association of this variant with increased binding of GATA1 that contribute to intensity of DNA curvature peaks and splitting pattern. These studies along with the meta-analysis strongly suggest that the rs7684318 variant contributes to the pathophysiology of PD by modulating binding of transcription factors related to Notch and Wnt signalling pathways that are likely to impair dopmanergic transmission.

引用

页数：8