Negative resultsLack of evidence for association of UQCRC1 with Parkinson's disease in Europeans
Introduction
The genetics of Parkinson's disease (PD) has been extensively studied over the last 20 years (Bandres-Ciga et al., 2020). A recent genome-wide association study (GWAS) identified 90 independent risk variants (Nalls et al., 2019); however, these variants explain less than 50% of the heritability of PD (Nalls et al., 2019), suggesting that other, unknown common and rare genetic variants affect the risk of PD. A novel variant p.Y314S in UQCRC1 encoding the ubiquinol-cytochrome c reductase core protein (UQCRC1) has been recently identified in 5 Taiwanese family members with parkinsonism by whole-exome sequencing (Lin et al., 2019). UQCRC1 is a mitochondrial protein and part of the respiratory chain III complex (Hoffman et al., 1993), which may play a role in mitochondrial respiration (Lin et al., 2019; Shan et al., 2019).
The purpose of this work is to examine the role of UQCRC1 in a large-scale European PD population using GWAS and whole-genome sequencing (WGS) data from the International Parkinson Disease Genomics Consortium (IPDGC) and Accelerating Medicines Partnership–Parkinson's disease (AMP-PD) initiative.
Section snippets
Methods
The study populations included 14,671 patients with PD and 17,667 controls from IPDGC and 1647 patients with PD and 1050 controls from AMP-PD (https://amp-pd.org/). Quality control of IPDGC GWAS data was performed on both individual and variant levels as previously described (Nalls et al., 2019). Similar quality control procedures were performed in the AMP-PD WGS data, as described by AMP-PD (https://amp-pd.org/whole-genome-data). We extracted UQCRC1 genotyping data from both data sets using
Results
Using the IPDGC GWAS data, we identified 140 common variants in the selected region (Fig. 1). None of the common variants annotated to UQCRC1 were associated with PD (Supplementary Table 1). In the AMP-PD WGS data, we identified 94 variants with MAF <0.03 within or close to UQCRC1 (Supplementary Table 2), including 9 nonsynonymous variants (Supplementary Table 2). We performed burden tests for 3 categories of variants: 1) all rare variants, 2) all rare coding variants, and 3) all rare
Discussion
In the present study, we performed a comprehensive analysis of common and rare variants in UQCRC1 using GWAS and WGS data from large cohorts of patients with PD and controls.
In the original study in which UQCRC1 variants were implicated, the authors described a family in which 5 carriers of UQCRC1 p.Y314S had late-onset levodopa responsive parkinsonism and axonal type sensorimotor polyneuropathy (Lin et al., 2019). In addition, autosomal dominant inheritance was demonstrated and there were no
Disclosure statement
Z.G-O. has received consulting fees from Lysosomal Therapeutics Inc., Idorsia, Prevail Therapeutics, Denali, Ono Therapeutics, Neuron23, Handl Therapeutics, Deerfield and Inception Sciences (now Ventus). None of these companies were involved in any parts of preparing, drafting, and publishing this study. Other authors have no additional disclosures to report.
CRediT authorship contribution statement
Konstantin Senkevich: Conceptualization, Data curation, Formal analysis, Methodology, Visualization, Writing - original draft. Sara Bandres-Ciga: Data curation, Resources, Formal analysis, Software, Writing - review & editing. Ziv Gan-Or: Conceptualization, Funding acquisition, Methodology, Resources, Supervision, Visualization, Writing - review & editing. Lynne Krohn: Conceptualization, Methodology, Project administration, Resources, Supervision, Visualization, Writing - review & editing.
Acknowledgements
We thank the participants for contributing to the study. We would like to also thank all members of the International Parkinson Disease Genomics Consortium (IPDGC). For a complete overview of members, acknowledgements, and funding, please see http://pdgenetics.org/partners. Data used in the preparation of this article were obtained from the AMP PD Knowledge Platform. For up-to-date information on the study, visit https://www.amp-pd.org." AMP-PD—a public-private partnership—is managed by the
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