Is SH3GL2 p.G276V the Causal Functional Variant Underlying Parkinson's Disease Risk at this Locus?

We read with great interest the article by Bademosi and colleagues,¹ 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 regulation.¹ Two SH3GL2 independent signals have been identified to potentially increase PD risk in the latest European genome-wide association studies (GWAS) meta-analysis: rs13294100 and rs10756907.²

Exome sequencing on a German cohort suggested the p.G276V variant as an independent PD risk factor. Bademosi et al¹ recently demonstrated that p.G276V impairs Ca2+ influx-induced synaptic autophagy without destabilizing EndoA1. 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's 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 10 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 assessed.^2-5 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 S1). Likewise, 30,719 variants were identified in GP2 (Supplementary Table S1). The p.G276V variant was found in Europeans in both AMP-PD (one case, two controls) and GP2 (three cases, one control); however, no association was found with PD risk (AMP-PD: P = 0.394, odds ratio [OR] = 1.296; GP2: P = 0.869, OR = 1.034) (Table 1). This variant was also identified in GP2 in three African American (AAC) controls and one Ashkenazi Jew (AJ) PD patient.

No linkage disequilibrium (LD) was observed between p.G276V and the European GWAS lead single nucleotide polymorphisms (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 populations.^{4, 5} The analysis of a multi-ancestry population³ identified the intronic variant rs910316833 as the most significant SNP (Supplementary Fig. S1).

The QTL analysis revealed six 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 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.

M.T.P. and S.B.C. conceived and designed the study. A.L.F., A.J.H.M., D.B.R.P., A.N.C. and M.B.M. performed the analysis of the results. A.L.F., A.J.H.M. and D.B.R.P. wrote the manuscript with support from A.N.C., M.B.M., S.B.C. and M.T.P. All authors contributed to the editing of the final manuscript.