Parkinson's disease age at onset genome-wide association study: Defining heritability, genetic loci, and α-synuclein mechanisms

Abstract

Background: Increasing evidence supports an extensive and complex genetic contribution to PD. Previous genome-wide association studies (GWAS) have shed light on the genetic basis of risk for this disease. However, the genetic determinants of PD age at onset are largely unknown.

Objectives: To identify the genetic determinants of PD age at onset.

Methods: Using genetic data of 28,568 PD cases, we performed a genome-wide association study based on PD age at onset.

Results: We estimated that the heritability of PD age at onset attributed to common genetic variation was ∼0.11, lower than the overall heritability of risk for PD (∼0.27), likely, in part, because of the subjective nature of this measure. We found two genome-wide significant association signals, one at SNCA and the other a protein-coding variant in TMEM175, both of which are known PD risk loci and a Bonferroni-corrected significant effect at other known PD risk loci, GBA, INPP5F/BAG3, FAM47E/SCARB2, and MCCC1. Notably, SNCA, TMEM175, SCARB2, BAG3, and GBA have all been shown to be implicated in α-synuclein aggregation pathways. Remarkably, other well-established PD risk loci, such as GCH1 and MAPT, did not show a significant effect on age at onset of PD.

Conclusions: Overall, we have performed the largest age at onset of PD genome-wide association studies to date, and our results show that not all PD risk loci influence age at onset with significant differences between risk alleles for age at onset. This provides a compelling picture, both within the context of functional characterization of disease-linked genetic variability and in defining differences between risk alleles for age at onset, or frank risk for disease. © 2019 International Parkinson and Movement Disorder Society.

Keywords: GBA; Parkinson's disease; SNCA; TMEM175; age at onset.

Figure1:. Manhattan plot of Parkinson’s disease age at onset GWAS.

Based on meta-analyses of datasets (n=28,568) using 7,426,111 SNPs. Two genome-wide significant loci were identified: SNCA and the TMEM175/GAK. Additionally, one borderline significant locus was found, APOE.

Figure2:. SNCA association with Parkinson’s disease age at onset.

A) Locus zoom plot of the association signal of the SNCA locus. The age at onset association signal is primarily based at the 3’ end of the SNCA gene, highly similar as the Parkinson’s disease GWAS signal of Chang et al 2017 (Supplementary Figure8). B) Conditional analysis based on the most associated SNP (rs356203) shows that there is a secondary signal at the 5’ end of the SNCA gene rs6532192, as well similar as previously reported for the Parkinson’s disease GWAS Chang et al 2017.

Figure3. TMEM175/GAK locus association with Parkinson’s disease age at onset and Parkinson’s disease.

A) Locus zoom plot of the association signal of the TMEM175/GAK locus with Parkinson’s disease age at onset. The association signal is primarily based on the coding variant TMEM175 p.M393T, rs34311866. B) Locuszoom plot of the association signal of the TMEM175/GAK locus with Parkinson’s disease vs controls Chang et al 2017. Similarly, as in A the main signal is based on the coding variant TMEM175 p.M393T, rs34311866.

Figure4:. P-value and beta value correlation plot between PD GWAS and age at onset GWAS.

A) Log transformed P-values were plotted of the Chang et al 2017 PD GWAS (x-axis) and the current age at onset GWAS (y-axis). SNPs are annotated by their closest gene. Green dots are loci that pass Bonferroni correction and red are loci that did not pass Bonferroni correction. B) Beta-values were plotted of the Chang et al 2017 PD GWAS (x-axis) and the current age at onset GWAS (y-axis). SNPs are annotated by their closest gene. Green dots are loci that pass Bonferroni correction and red are loci that did not pass Bonferroni correction.

Figure5:. Minor allele frequency differences correlated with age groups separated by case-control status.

Genotype data was merged and minor allele frequency were calculated per age group and separated by case control status (IPDGC data only: N_cases=17,996 and N_controls=16,502, each age group contains >850 individuals). Lines were using LOESS regressions based on the minor allele frequency per age group. On the left the three most significant loci associated with PD age at onset are shown; SNCA=rs356203, TMEM175/GAK=rs34311866 and APOE=rs429358. On the right three significant PD case control GWAS loci are shown to have no clear effect on PD age at onset; MAPT=rs17649553, RAB7L1=rs823118, GCH1= rs11158026. Standard error-bars are not shown in figurebut are neglectable(~0.015) for each age-group.