Targeted sequencing of Parkinson’s disease loci genes highlights SYT11, FGF20 and other associations

Abstract

Genome-wide association studies (GWAS) have identified numerous loci associated with Parkinson’s disease. The specific genes and variants that drive the associations within the vast majority of these loci are unknown. We aimed to perform a comprehensive analysis of selected genes to determine the potential role of rare and common genetic variants within these loci. We fully sequenced 32 genes from 25 loci previously associated with Parkinson’s disease in 2657 patients and 3647 controls from three cohorts. Capture was done using molecular inversion probes targeting the exons, exon-intron boundaries and untranslated regions (UTRs) of the genes of interest, followed by sequencing. Quality control was performed to include only high-quality variants. We examined the role of rare variants (minor allele frequency < 0.01) using optimized sequence Kernel association tests. The association of common variants was estimated using regression models adjusted for age, sex and ethnicity as required in each cohort, followed by a meta-analysis. After Bonferroni correction, we identified a burden of rare variants in SYT11, FGF20 and GCH1 associated with Parkinson’s disease. Nominal associations were identified in 21 additional genes. Previous reports suggested that the SYT11 GWAS association is driven by variants in the nearby GBA gene. However, the association of SYT11 was mainly driven by a rare 3′ UTR variant (rs945006601) and was independent of GBA variants (P = 5.23 × 10−5 after exclusion of all GBA variant carriers). The association of FGF20 was driven by a rare 5′ UTR variant (rs1034608171) located in the promoter region. The previously reported association of GCH1 with Parkinson’s disease is driven by rare non-synonymous variants, some of which are known to cause dopamine-responsive dystonia. We also identified two LRRK2 variants, p.Arg793Met and p.Gln1353Lys, in 10 and eight controls, respectively, but not in patients. We identified common variants associated with Parkinson’s disease in MAPT, TMEM175, BST1, SNCA and GPNMB, which are all in strong linkage disequilibrium with known GWAS hits in their respective loci. A common coding PM20D1 variant, p.Ile149Val, was nominally associated with reduced risk of Parkinson’s disease (odds ratio 0.73, 95% confidence interval 0.60–0.89, P = 1.161 × 10−3). This variant is not in linkage disequilibrium with the top GWAS hits within this locus and may represent a novel association. These results further demonstrate the importance of fine mapping of GWAS loci, and suggest that SYT11, FGF20, and potentially PM20D1, BST1 and GPNMB should be considered for future studies as possible Parkinson’s disease-related genes.

The Genetics of Parkinson’s Disease and Implications for Clinical Practice

“…Because it relies upon arrays of directly genotyped variants and then imputes other variants by linkage disequilibrium, important disease associated variants can be missed. In fact, GWAS was only able to identify the GBA locus using a candidate gene approach [ 145 ]. It may be that other such genetic risk factors contribute to PD risk but remain undetected by current GWAS analyses.…”

Clinical and Genetic Analysis of Costa Rican Patients With Parkinson's Disease

“…Rare variants (MAF < 0.01) with a minimum depth of coverage of > 30× were included in the analysis, along with common variants (MAF ≥ 0.01) with >15× coverage. We have established that for common variants, we get reliable reads at 15×; however, to get reliable reads for rare variants, we need > 30×; otherwise, there are many false positives ( 40 ). Variant calls with a genotype frequency of <25% of the reads or genotype quality of <30 were excluded.…”

“…For rare variants' analysis, we examined the burden of rare variants in each gene using optimized sequence Kernel association test (SKAT-O) adjusted for age and sex ( 41 ). Rare variants were separated into different categories based on their potential pathogenicity to examine specific enrichment in different variant subgroups as described previously ( 40 ): (1) variants with Combined Annotation Dependent Depletion (CADD) score of ≥12.37 (representing the top 2% of potentially deleterious variants) ( 42 ); (2) regulatory variants predicted by ENCODE ( 43 ); (3) potentially functional variants including all non-synonymous variants, stop gain/loss variants, frameshift variants, and intronic splicing variants located within two base pairs of exon–intron junctions; (4) loss-of-function variants, which includes stop gain/loss, frameshift, and splicing variants; and (5) only non-synonymous variants. Bonferroni correction for multiple comparisons was applied as necessary.…”

The Association Between Lysosomal Storage Disorder Genes and Parkinson’s Disease: A Large Cohort Study in Chinese Mainland Population

“…Therefore, it needs more attention in the follow-up experimental functional studies in PD. Specifically, the association of variants of the SCARB2 gene and PD was previously reported (Nalls et al, 2014;Alcalay et al, 2016;Rudakou et al, 2021) in European cohorts. SCARB2 encodes the membrane protein required for correct targeting of glucocerebrosidase (GCase) to the lysosome (Zeigler et al, 2014).…”