Genome-wide Association and Meta-analysis of Age at Onset in Parkinson Disease: Evidence From the COURAGE-PD Consortium.

Abstract

Considerable heterogeneity exists in the literature concerning genetic determinants of the age at onset (AAO) of Parkinson disease (PD), which could be attributed to a lack of well-powered replication cohorts. The previous largest genome-wide association studies (GWAS) identified <i>SNCA</i> and <i>TMEM175</i> loci on chromosome (Chr) 4 with a significant influence on the AAO of PD; these have not been independently replicated. This study aims to conduct a meta-analysis of GWAS of PD AAO and validate previously observed findings in worldwide populations. 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 by combining our study with the largest publicly available European ancestry dataset compiled by the International Parkinson Disease Genomics Consortium (IPDGC). The COURAGE-PD Consortium included a cohort of 8,535 patients with PD (91.9%: Europeans and 9.1%: East Asians). The average AAO in the COURAGE-PD dataset was 58.9 years (SD = 11.6), with an underrepresentation 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 (<i>p</i> < 5 × 10^-8). Nevertheless, the COURAGE-PD dataset confirmed the role of the previously published <i>TMEM175</i> variant as a genetic determinant of the AAO of PD with Bonferroni-corrected nominal levels of significance (<i>p</i> < 0.025): (rs34311866: β(SE)_COURAGE = 0.477(0.203), <i>p</i> _COURAGE = 0.0185). The subsequent meta-analysis of COURAGE-PD and IPDGC datasets (N_total = 25,950) led to the identification of 2 genome-wide significant association signals on Chr 4, including the previously reported <i>SNCA</i> locus (rs983361: β(SE)_{COURAGE+IPDGC} = 0.720(0.122), <i>p</i> _{COURAGE+IPDGC} = 3.13 × 10^-9) and a novel <i>BST1</i> locus (rs4698412: β(SE)_{COURAGE+IPDGC} = -0.526(0.096), <i>p</i> _{COURAGE+IPDGC} = 4.41 × 10^-8). Our study further refines the genetic architecture of Chr 4 underlying the AAO of the PD phenotype through the identification of <i>BST1</i> as a novel AAO PD locus. These findings open a new direction for the development of treatments to delay the onset of PD.