We read with great interest the article by Bademosi and colleagues1, where they investigated the role of SH3GL2 p.G276V on neuron dysfunction in Parkinson’s disease (PD).
The SH3GL2 gene encodes the Endophilin-A1 (EndoA1) protein, crucial for synaptic vesicle endocytosis and blood-brain barrier permeability regulation1. Two SH3GL2 independent signals have been identified to potentially increase PD risk in the latest European GWAS-meta-analysis: rs13294100 and rs107569072.
Exome sequencing on a German cohort suggested the p.G276V variant as an independent PD risk factor. Bademosi et al. recently demonstrated that p.G276V impairs Ca2+ influx-induced synaptic autophagy without destabilizing EndoA11. The authors found that the human p.G276V protein was stable but showed a significant decrease in the number of autophagosomes compared with control neurons.
To clarify the association between SH3GL2 and PD, we leveraged whole-genome sequencing (WGS) data from the Accelerating Medicines Partnership – Parkinson Disease (AMP-PD) (https://amp-pd.org/) release 3.0, consisting of 3,105 cases and 3,670 controls from European descent, and large-scale genotyping imputed data from the Global Parkinson’s Genetics Program (GP2; https://gp2.org/) release 5.0, consisting of 12,728 cases and 10,533 controls from ten different ancestries. Quality control analyses are described elsewhere [https://github.com/vitale199/GenoTools/]. Variants were annotated using ANNOVAR, and Fisher’s exact test was applied using PLINK 1.9. Summary statistics from the latest PD risk GWAS meta-analyses were assessed2–5. We leveraged data from the omicSynth data resource looking at quantitative trait loci (QTL). Gene-based burden analyses were performed by using RVTESTS.
We identified 14,590 SH3GL2 variants in AMP-PD (Supplementary Table 1). Likewise, 30,719 variants were identified in GP2 (Supplementary Table 1). The p.G276V variant was found in Europeans in both AMP-PD (1 case, 2 controls) and GP2 (3 cases, 1 control); however, no association was found with PD risk (AMP-PD: p=0.394, OR=1.296; GP2: p=0.869, OR=1.034) (Table 1). This variant was also identified in GP2 in 3 African American (AAC) controls and 1 Ashkenazi Jew (AJ) PD patient.
Table 1.
SH3GL2 p.Gly276Val variant identified in the AMP-PD and GP2 datasets.
| Locationa | Variant | A1 | A2 | Cohort | F (Cases) | F (Controls) | OR (95% CI) |
P-value |
|---|---|---|---|---|---|---|---|---|
| 9: 17793465 | p.Gly276Val rs150543523 |
T |
G |
AMP PD | 0.003275 | 0.002528 | 1.296 | 0.3944 |
| GP2 AAC | 0 | 0.001455 | NA | 0.3589 | ||||
| GP2 AFR | 0 | 0 | NA | NA | ||||
| GP2 AJ | 0.000676 | 0 | NA | 0.4701 | ||||
| GP2 AMR | 0 | 0 | NA | NA | ||||
| GP2 CAS | 0 | 0 | NA | NA | ||||
| GP2 EUR | 0.003955 | 0.003828 | 1.034 (0.69780–1.531) | 0.8693 | ||||
| GP2 SAS | 0 | 0 | NA | NA | ||||
| GP2 MDE | 0 | 0 | NA | NA | ||||
| GP2 FIN | 0 | 0 | NA | NA |
Chromosomal location is given according to GRCh38/hg38.
A1 = Effect allele
A2 = Reference allele
F = Allele frequency (A1)
OR (95% CI) = Odds ratio with 95% confidence intervals
No linkage disequilibrium (LD) was observed between p.G276V and the European GWAS lead SNPs. Conditional analyses suggested that these variants were most likely independent signals. No significant association between SH3GL2 common genetic variation and PD risk was identified in the Latino nor Asian populations4,5. The analysis of a multi-ancestry population3 identified the intronic variant rs910316833 as the most significant SNP (Supplementary Figure 1).
The QTL analysis revealed 6 potential functional impacts for SH3GL2 (top SNPs: rs2145659, rs3758217, rs10756899 and rs2383044). Finally, no cumulative effect of multiple genetic variants within SH3GL2 on PD risk was found after conducting rare variant burden meta-analyses.
Using the largest case-control genetic cohorts publicly available to date in the PD field, the p.G276V variant originally reported by Germer et al. was found in both AMP-PD and GP2 in Europeans; however, this variant was not associated with PD risk and consequently does not causally explain the PD GWAS significant association at the SH3GL2 locus.
Supplementary Material
Acknowledgments
This work was carried out with the support and guidance of the ‘GP2 Trainee Network’ which is part of the Global Parkinson’s Genetics Program and funded by the Aligning Science Across Parkinson’s (ASAP) initiative. Data used in the preparation of this article were obtained from Global Parkinson’s Genetics Program (GP2). For a complete list of GP2 members, see https://gp2.org. Data used in the preparation of this article were obtained from the Accelerating Medicines Partnership® (AMP®) Parkinson’s Disease (AMP® PD) Knowledge Platform. For up-to-date information on the study, visit https://www.amp-pd.org. ACCELERATING MEDICINES PARTNERSHIP and AMP are registered service marks of the US Department of Health and Human Services.
Funding
This research was supported in part by the Intramural Research Program of the NIH, National Institute on Aging (NIA), National Institutes of Health, Department of Health and Human Services; project number ZO1 AG000535 and ZIA AG000949, as well as the National Institute of Neurological Disorders and Stroke (NINDS) and the National Human Genome Research Institute (NHGRI). Data used in the preparation of this article were obtained from Global Parkinson’s Genetics Program (GP2; https://gp2.org). GP2 is funded by the Aligning Science Across Parkinson’s (ASAP) initiative and implemented by The Michael J. Fox Foundation for Parkinson’s Research. Additional funding was provided by The Michael J. Fox Foundation for Parkinson’s Research through grant MJFF-009421/17483. The AMP® PD program is a public-private partnership managed by the Foundation for the National Institutes of Health and funded by the National Institute of Neurological Disorders and Stroke (NINDS) in partnership with the Aligning Science Across Parkinson’s (ASAP) initiative; Celgene Corporation, a subsidiary of Bristol-Myers Squibb Company; GlaxoSmithKline plc (GSK); The Michael J. Fox Foundation for Parkinson’s Research; Pfizer Inc.; Sanofi US Services Inc.; and Verily Life Sciences.
Footnotes
Competing interests
The authors report no competing interests.
Data Sharing
All GP2 data is hosted in collaboration with the Accelerating Medicines Partnership in Parkinson’s disease, and is available via application on the website (https://amp-pd.org/register-for-amp-pd; https://doi.org/10.5281/zenodo.7904832). Genotyping imputation, quality control, ancestry prediction, and processing was performed using GenoTools v1.0, publicly available on GitHub (https://github.com/GP2code/GenoTools). All scripts for analyses are publicly available on GitHub [https://github.com/GP2-TNC-WG/GP2_TRAINEES-SH3GL2/; Zenodo DOI: https://doi.org/10.5281/zenodo.10257319].
References
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
All GP2 data is hosted in collaboration with the Accelerating Medicines Partnership in Parkinson’s disease, and is available via application on the website (https://amp-pd.org/register-for-amp-pd; https://doi.org/10.5281/zenodo.7904832). Genotyping imputation, quality control, ancestry prediction, and processing was performed using GenoTools v1.0, publicly available on GitHub (https://github.com/GP2code/GenoTools). All scripts for analyses are publicly available on GitHub [https://github.com/GP2-TNC-WG/GP2_TRAINEES-SH3GL2/; Zenodo DOI: https://doi.org/10.5281/zenodo.10257319].