Grover, Sandeep, Kumar Sreelatha, Ashwin Ashok, Pihlstrom, Lasse, Domenighetti, Cloe, Schulte, Claudia, Sugier, Pierre-Emmanuel, Radivojkov-Blagojevic, Milena, Lichtner, Peter, Mohamed, Oceane, Portugal, Berta et al (show 73 more authors)
(2022)
Genome-wide Association and Meta-analysis of Age at Onset in Parkinson Disease Evidence From the COURAGE-PD Consortium.
NEUROLOGY, 99 (7).
E698-E710.
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Abstract
<h4>Background and objectives</h4>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.<h4>Methods</h4>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).<h4>Results</h4>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<sup>-8</sup>). 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)<sub>COURAGE</sub> = 0.477(0.203), <i>p</i> <sub>COURAGE</sub> = 0.0185). The subsequent meta-analysis of COURAGE-PD and IPDGC datasets (N<sub>total</sub> = 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)<sub>COURAGE+IPDGC</sub> = 0.720(0.122), <i>p</i> <sub>COURAGE+IPDGC</sub> = 3.13 × 10<sup>-9</sup>) and a novel <i>BST1</i> locus (rs4698412: β(SE)<sub>COURAGE+IPDGC</sub> = -0.526(0.096), <i>p</i> <sub>COURAGE+IPDGC</sub> = 4.41 × 10<sup>-8</sup>).<h4>Discussion</h4>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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | and the Comprehensive Unbiased Risk Factor Assessment for Genetics and Environment in Parkinson's Disease (COURAGE-PD) Consortium, Humans, Parkinson Disease, Genetic Predisposition to Disease, Age of Onset, Polymorphism, Single Nucleotide, Female, Genome-Wide Association Study, Courage |
| Divisions: | Faculty of Health and Life Sciences Faculty of Health and Life Sciences > Institute of Systems, Molecular and Integrative Biology |
| Depositing User: | Symplectic Admin |
| Date Deposited: | 26 Oct 2022 14:17 |
| Last Modified: | 18 Jan 2023 19:49 |
| DOI: | 10.1212/WNL.0000000000200699 |
| Related URLs: | |
| URI: | https://livrepository.liverpool.ac.uk/id/eprint/3165794 |
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