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

SNCAandmTORPathway Single Nucleotide Polymorphisms Interact to Modulate the Age at Onset of Parkinson's Disease

“…These findings are largely consistent with the most recent meta-analysis of PD AAO to date. 50 Previously, the SNCA rs356219 was shown to modulate the AAO of IPD in the German population (3 years difference; 55.7 years for GG vs 58.7 years for AA) 13 and also in another Northern Spain cohort genotyping of the SNCA 3'UTR neighboring marker rs356165, which is in absolute linkage disequilibrium with rs356219 (3.5 years difference; 60.1 years for GG vs 56.6 for AA). 47 The most recent meta-analysis of PD AAO to date has reported a similar effect for the SNCA 3'UTR rs356203 marker, yet with a slighter AAO effect of 0.6 years difference, probably because of the larger diversity of populations screened in this study.…”

Parkinson's disease, aging and adult neurogenesis: Wnt/β‐catenin signalling as the key to unlock the mystery of endogenous brain repair

“…Aging is the leading risk factor for Parkinson's disease (PD), the second most diagnosed neurodegenerative disorder (ND), affecting almost 1% of the population over age 60 (Blauwendraat et al, ). Typical neuropathological hallmarks of PD include the selective loss of dopaminergic (DAergic) cell bodies in the subtantia nigra pars compacta (SNpc) in the mesencephalon and their projections to the striatum (Str), with consequent depletion of striatal dopamine (DA), the deposition of cytoplasmic fibrillary inclusions (Lewy bodies) containing ubiquitin and α‐synuclein (α‐syn), and astroglial activation (Schapira et al, ).…”

“…Significantly, approximately 10% of PD cases can be directly attributed to genetic factors, associated with mutations in genes including α ‐synuclein ( SNCA ), E3 ubiquitin‐protein ligase parkin ( PRKN ), ubiquitin C‐terminal hydrolase L1 ( UCHL1 ), PTEN‐induced putative kinase ( PINK1 ), DJ‐1 ( PARK7 ), leucine‐rich‐repeat kinase 2 ( LRRK2 ), vacuolar protein sorting 35 homolog gene ( VPS35 ), and β‐glucocerebrosidase 1 ( GBA1 ), linked to autosomal dominant late‐onset. In contrast, the etiology of the vast majority (up to 90%) of so called “idiopathic” PD cases is multifactorial, likely arising from a combination of polygenic inheritance and environmental exposures, with gene‐environment interactions playing a decisive role in PD onset and/or progression (Blauwendraat et al, ; Cannon & Greenamyre, ; Dzamko, Geczy, & Halliday, ; Guttuso, Andrzejewski, Lichter, & Andersen, ; Langston, ; Lastres‐Becker et al, ; L’Episcopo, Tirolo, Testa et al ; Marchetti and Abbracchio, ).…”

“…Aging is the leading risk factor for Parkinson's disease (PD), the second most diagnosed neurodegenerative disorder (ND), affecting almost 1% of the population over age 60 (Blauwendraat et al, 2019).…”

Synuclein Meeting 2019: where we are and where we need to go

“…Over the years, our understanding of the genetics of PD has evolved tremendously and other mutations in the SNCA gene (point mutations and multiplications) have been linked to familial forms of the disease (Polymeropoulos et al ; Kruger et al ; Singleton et al ; Zarranz et al ; Chartier‐Harlin et al ; Appel‐Cresswell et al ; Proukakis et al ; Lesage et al ; Fares et al ; Pasanen et al ). More recently, polymorphisms in the SNCA gene have been identified as risk factors for PD, in genome wide association studies (Nalls et al ; Blauwendraat et al ). For these reasons, aSyn took center stage, and has been the subject of intense research over the past 22 years.…”