Abstract
Many common genetic factors have been identified to contribute to Parkinson's disease (PD) susceptibility, improving our understanding of the related underlying biological mechanisms. The involvement of rarer variants in these loci has been poorly studied. Using International Parkinson's Disease Genomics Consortium data sets, we performed a comprehensive study to determine the impact of rare variants in 23 previously published genome-wide association studies (GWAS) loci in PD. We applied Prix fixe to select the putative causal genes underneath the GWAS peaks, which was based on underlying functional similarities. The Sequence Kernel Association Test was used to analyze the joint effect of rare, common, or both types of variants on PD susceptibility. All genes were tested simultaneously as a gene set and each gene individually. We observed a moderate association of common variants, confirming the involvement of the known PD risk loci within our genetic data sets. Focusing on rare variants, we identified additional association signals for LRRK2, STBD1, and SPATA19. Our study suggests an involvement of rare variants within several putatively causal genes underneath previously identified PD GWAS peaks.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 220.e11-220.e18 |
| Journal | Neurobiology of Aging |
| Volume | 59 |
| DOIs | |
| State | Published - Nov 2017 |
Funding
The Rotterdam Study is funded by Erasmus Medical Center and Erasmus University, Rotterdam, Netherlands Organization for the Health Research and Development (ZonMw), the Research Institute for Diseases in the Elderly (RIDE), the Ministry of Education, Culture, and Science, the Ministry for Health, Welfare and Sports, the European Commission (DG XII), and the Municipality of Rotterdam. The authors are grateful to the study participants, the staff from the Rotterdam Study, and the participating general practitioners and pharmacists. This study is also supported by the Courage-PD is an EU Joint Programme—Neurodegenerative Disease Research (JPND) project (MS, TG). The project is supported through the following funding organizations under the aegis of JPND– www.jpnd.eu : the Medical Research Council, United Kingdom, the French National Research Agency, the German Bundesministerium für Bildung und Forschung, the Italian Ministry of Health/Ministry of Education, Universities and Research, the Israeli Ministry of Health, the Luxembourgian National Research Fund, the Netherlands Organisation for Health Research and Development, the Research Council of Norway, the Portuguese Foundation for Science and Technology, and the Spanish National Institute of Health Carlos III. The generation and management of the exome sequencing data for the Rotterdam Study was executed by the Human Genotyping Facility of the Genetic Laboratory of the Department of Internal Medicine, Erasmus MC, the Netherlands. The Exome Sequencing data set was funded by the Netherlands Genomics Initiative (NGI)/Netherlands Organisation for Scientific Research (NWO) sponsored Netherlands Consortium for Healthy Aging (NCHA; project nr. 050-060–810), by the Genetic Laboratory of the Department of Internal Medicine, Erasmus MC, and by a Complementation Project of the Biobanking and Biomolecular Research Infrastructure Netherlands (BBMRI-NL; www.bbmri.nl ; project number CP2010-41). The authors also thank Mr. Pascal Arp, Ms. Mila Jhamai, BSc, and Mr. Marijn Verkerkj for their help in creating the RS-Exome Sequencing database. This work was supported in part by the Prinses Beatrix Spierfonds (IEJ and PH). MS is supported by the Michael J Fox Foundation, USA. TG and PH were supported by the Federal Ministry of Education and Research (BMBF) under the grant numbers 031A430A (TG) and 031A430D (PH) (e:Med Module II). This work was supported in part by the Intramural Research Program of the National Institute on Aging, National Institutes of Health, Department of Health and Human Services; project ZO1 AG000949. Mike A. Nalls' participation is supported by a consulting contract between Data Tecnica International and the National Institute on Aging, NIH, Bethesda, MD, USA. As a possible conflict of interest, Dr Nalls also consults for Illumina Inc, the Michael J. Fox Foundation, and University of California Healthcare among others.
Keywords
- Common risk loci
- Parkinson's disease
- Rare variants
- Variant aggregation test
- Whole exome sequencing
ASJC Scopus subject areas
- Clinical Neurology
- Geriatrics and Gerontology
- Aging
- General Neuroscience
- Developmental Biology