Introduction
Previous studies have identified several familial PD genes such as SNCA and LRRK2 in the European population. However, records of any comparative study to evaluate the extent of genetic risk between the Asian and European population are lacking.
Objective
To identify novel genome-wide significant loci for PD in Asian individuals and to compare genetic risk between Asian and European cohorts.
Patients and Methods
A meta-analysis consisting of genome-wide association data of 31,575 individuals (6,724 PD cases & 24,851 controls), collected from January 1, 2016, to December 31, 2018, was conducted.
Results
- 11 genome-wide significant loci were identified, out of which 9 were identified previously including PARK16, ITPKB, MCCC1, SNCA, FAM47E-SCARB2, DLG2, LRRK2, RIT2 and FYN.
- Other 2 were new associations identified at SV2C and WBSCR17.
- A powerful association at 7 other loci viz., GBA -SYT11, BST1, TMEM175-GAK-DGKQ, ZNF184, FGF20, VPS13C and ASXL3 were identified which had previously been reported to be associated with PD in European individuals.
- Amongst the 16 previously reported loci, the SNV was in high linkage disequilibrium (LD) with the European SNV.
- Allelic heterogeneity was observed at LRRK2, ITPKB, ZNF184, FAM47E-SCARB2 and GBA/SYT11 and LD differences were observed at SNCA, FYN, VPS13C, and ASXL3 highlighting the difference in the genetic architecture between the Asian and European individuals.
- A genome-wide significant association at rs246814 located within an intron of the SV2C gene was observed.
- The SNV was in complete LD with a missense variant p.Asp543Asn within SV2C and even though this change was perceived as benign, there was a possibility that it could affect the N-linked glycosylation.
- Genome-wide significant association was observed at a second novel locus tagged by rs9638616. This SNV was found to be located within an intron of the WBSCR17 gene and near genes encoding microRNAs mir-3914-1 and mir3914-2.
- Amongst the 78 SNVs polymorphic in Asian samples, genome-wide significant association in Asian individuals was only shown by 3 SNV’s.
- The direction of association and strong enrichment of SNV’s demonstrate substantial but incomplete overlap in genetic risk between the Asian and European populations.
- Both of the novel SNV’s were present at lower frequencies in European population as compared to the Asian population.
- The WBSCR17 SNV rs9638616 did not appear to be associated with PD risk.
- Higher SV2C expression was found in the substantia nigra, striatum and hypothalamus compared to the other regions in the brain.
- WBSCR17 demonstrated increased expression throughout multiple regions of the brain but there was no evidence for the corelation of the 2 novel SNVs (rs246814 and rs9638616) with gene expression levels in the brain or other relevant tissues.
- In the weighted polygenic risk score distribution, higher polygenic risk scores were significantly associated with a younger age of onset in patients with PD.
- A 0.29-year decrease in age of onset was estimated for every additional copy of risk allele present amongst the 11 loci.
Figure 1. Polygenic Risk Score (PRS) Analysis in Asian Samples. A) Polygenic risk score distribution using 11 genome-wide significant Asian single-nucleotide variant (SNVs) (formerly, SNP) and 90 known Parkinson disease SNVs (78 polymorphic); B) identified in European samples and C) receiver operator curve based on polygenic risk prediction of Parkinson disease with previously reported SNVs (black) (area under the curve [AUC], 60.2%) vs combined European and Asian SNVs (orange) (AUC, 63.1%).
Conclusion
The study identified two novel gene loci and defined the association between the SV2C missense allele and increased risk of PD, demonstrating SV2C as a potential therapeutic target.