Genome-wide Association and Meta-analysis of Age at Onset in Parkinson Disease

Abstract

Background and Objectives:Considerable heterogeneity exists in the literature concerning genetic determinants of the age of onset (AAO) of Parkinson’s disease (PD), which could be attributed to lack of well-powered replication cohorts. The previous largest GWAS identified SNCA and TMEM175 loci on chromosome (Chr) 4 with a significant influence on AAO of PD, these have not been independently replicated. The present study aims to conduct a meta-analysis of GWAS of PD AAO and validate previously observed findings in worldwide populations.Methods:A meta-analysis was performed on PD AAO GWAS of 30 populations of predominantly European ancestry from the Comprehensive Unbiased Risk Factor Assessment for Genetics and Environment in Parkinson's Disease (COURAGE-PD) consortium. This was followed up by combining our study with the largest publicly available European ancestry dataset compiled by the International Parkinson disease Genomics Consortium (IPDGC).Results:The COURAGE-PD included a cohort of 8,535 patients with PD (91.9%: Europeans, 9.1%: East-Asians). The average AAO in the COURAGE-PD dataset was 58.9 years (SD=11.6), with an under-representation of females (40.2%). The heritability estimate for AAO in COURAGE-PD was 0.083 (SE=0.057). None of the loci reached genome-wide significance (P<5x10-8). Nevertheless, the COURAGE-PD dataset confirmed the role of the previously published TMEM175 variant as genetic determinant of AAO of PD with Bonferroni-corrected nominal levels of significance (P<0.025): (rs34311866:β(SE)COURAGE=0.477(0.203), PCOURAGE=0.0185). The subsequent meta-analysis of COURAGE-PD and IPDGC datasets (Ntotal=25,950) led to the identification of two genome-wide significant association signals on Chr 4, including the previously reported SNCA locus (rs983361:β(SE)COURAGE+IPDGC=0.720(0.122), PCOURAGE+IPDGC=3.13x10-9) and a novel BST1 locus (rs4698412:β(SE)COURAGE+IPDGC=-0.526(0.096), PCOURAGE+IPDGC=4.41x10-8).Discussion:Our study further refines the genetic architecture of Chr 4 underlying the AAO of the PD phenotype through the identification of BST1 as a novel AAO PD locus. These findings open a new direction for the development of treatments to delay the onset of PD.

Genetic Evidence for Endolysosomal Dysfunction in Parkinson’s Disease: A Critical Overview

“…In the past two decades, PD etiopathogenesis has been linked with several deranged cellular mechanisms, ranging from mitochondrial impairment ( PRKN , PINK1 , PARK7 ) and ubiquitination defects ( FBXO7 ) to dysfunction of the endolysosomal pathway ( LRRK2 , VPS35 , VPS13C , ATP13A2 ) and synaptic vesicle trafficking ( SNCA , RAB39B , SYNJ1 , DNAJC6 ). In addition, significant parts of the risk genes associated with PD encode for endolysosomal and synaptic vesicle proteins, confirming a particular susceptibility of PD-related brain structures to the impairment of these pathways ( Figure 1 ) [ 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 ].…”

Common and Rare Variants in TMEM175 Gene Concur to the Pathogenesis of Parkinson’s Disease in Italian Patients

“…The TMEM175 gene is located on chromosome 4 in the TMEM175/GAK/DGKQ GWAS locus associated with PD [ 9 ]. Recently, the TMEM175 p.M393T common variant was described as a risk factor for PD in several populations [ 11 , 14 ], and rare deleterious variants were associated with PD in Italian families [ 8 ].…”

“…TMEM175 , one of the novel genes identified in our cohort of PD families, is located in a highly significant PD GWAS peak at chromosome 4 [ 9 , 10 ]. Recently, two common coding variants, rs34884217 (c.A194C, p.Q65P) and rs34311866 (c.T1178C, p.M393T), have been associated with PD risk in several populations [ 11 – 14 ]. This gene encodes for an endolysosomal K + channel that is involved in K + conductance, pH stability, and α-synuclein clearance [ 15 – 18 ].…”

Genetic architecture of Parkinson’s disease subtypes – Review of the literature

“…In 2019, the largest GWAS in PD, involving almost 38 thousand patients, found 90 common independent variants, which together accounted for 16–36% of the observed PD heritability ( Nalls et al, 2019 ). Recently, a large meta-analysis on PD GWAS on 8,535 patients revealed that polymorphisms of the TMEM175 (rs34311866), SNCA (rs983361), and BST1 (rs4698412) correlated with the age of the disease onset ( Grover et al, 2022 ).…”