Alpha synuclein (SNCA) rs7684318 variant contributes to Parkinson's disease risk by altering transcription factor binding related with Notch and Wnt signaling. (17th April 2021)

• Record Type: Journal Article
• Authors: Naushad, Shaik Mohammad; Hussain, Tajamul; Alrokayan, Salman; Kutala, Vijay Kumar
• Is Part Of: Neuroscience letters. Volume 750(2021)
• Publication Date: 2021-04-17
• Subjects: Alpha synuclein -- rs7684318 -- Parkinson's disease -- Meta-analysis -- DNase footprint analysis -- Transcription factor binding -- Notch signalling -- Wnt-beta catenin signalling; Neurology -- Periodicals; Neurology -- Periodicals; Research -- Periodicals; Neurologie -- Périodiques; Neuroanatomie -- Périodiques; Neuropharmacologie -- Périodiques; Neurophysiologie -- Périodiques; Neurology; Periodicals; Electronic journals; 617.48
• DOI: 10.1016/j.neulet.2021.135802
• Languages: English
• ISSNs: 0304-3940

Abstract

Highlights: Association studies of SNCA rs7684318 with PD were inconsistent. Meta-analysis confirmed the association of rs7684318 with PD. rs7684318 increased binding of RBPJ and GATA. It decreased binding of NKX2, SNAI2, SNAI3, DMRT1, HOX, WT1, POU4. Notch and Wnt signalling might be affected due to this variant. Abstract: 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.