Alpha synuclein (SNCA) rs7684318 variant contributes to Parkinson's disease risk by altering transcription factor binding related with Notch and Wnt signaling.
PMID 33705925 | DOI 10.1016/j.neulet.2021.135802 · Neuroscience letters · 2021
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 (Tau2: 0.0576, H: 2.32, I2: 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.
Validated evidence
| Type | Entity | Source evidence | Confidence | Extractor |
|---|---|---|---|---|
| gene | SNCA | “Alpha synuclein (SNCA) rs7684318 variant contributes to Parkinson's disease risk by altering transcription factor binding related with Notch and Wnt signaling.” | 0.98 | hgnc_dict_v1 |
| gene | RBPJ | “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.” | 0.98 | hgnc_dict_v1 |
| gene | SNAI2 | “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.” | 0.98 | hgnc_dict_v1 |
| gene | SNAI3 | “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.” | 0.98 | hgnc_dict_v1 |
| gene | DMRT1 | “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.” | 0.98 | hgnc_dict_v1 |
| gene | HOXA13 | “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.” | 0.98 | hgnc_dict_v1 |
| gene | HOXB13 | “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.” | 0.98 | hgnc_dict_v1 |
| gene | HOXC13 | “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.” | 0.98 | hgnc_dict_v1 |
| gene | HOXD13 | “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.” | 0.98 | hgnc_dict_v1 |
| gene | POU4F1 | “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.” | 0.98 | hgnc_dict_v1 |
| gene | POU4F2 | “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.” | 0.98 | hgnc_dict_v1 |
| gene | POU4F3 | “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.” | 0.98 | hgnc_dict_v1 |
| gene | GATA1 | “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.” | 0.98 | hgnc_dict_v1 |
| phenotype | Parkinson disease | “Alpha synuclein (SNCA) rs7684318 variant contributes to Parkinson's disease risk by altering transcription factor binding related with Notch and Wnt signaling.” | 0.93 | phenotype_alias_lexicon_v2 |
| variant | rs7684318 | “Alpha synuclein (SNCA) rs7684318 variant contributes to Parkinson's disease risk by altering transcription factor binding related with Notch and Wnt signaling.” | 0.90 | hgvs_regex_v1 |