Identification of novel variants, genes and pathways potentially linked to Parkinson’s disease using machine learning

There are 78 loci associated with Parkinson’s disease (PD) in the most recent genome-wide association study (GWAS), yet the specific genes driving these associations are mostly unknown. Herein, we aimed to nominate the top candidate gene from each PD locus, and identify variants and pathways potentially involved in PD. We trained a machine learning model to predict PD-associated genes from GWAS loci using genomic, transcriptomic, and epigenomic data from brain tissues and dopaminergic neurons. We nominated candidate genes in each locus, identified novel pathways potentially involved in PD, such as the inositol phosphate biosynthetic pathway ( INPP5F , IP6K2 , ITPKB, PPIP5K2 ). Specific common coding variants in SPNS1 and MLX may be involved in PD, and burden tests of rare variants further support that CNIP3 , LSM7 , NUCKS1 and the polyol/inositol phosphate biosynthetic pathway are associated with PD. Functional studies are needed to further analyze the involvements of these genes and pathways in PD. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This work was financially supported by the Michael J. Fox Foundation, Parkinson's Society Canada, the Canadian Consortium on Neurodegeneration in Aging (CCNA), Canadian Institutes of Health Research (#476751), and the Canada First Research Excellence Fund (CFREF) awarded to McGill University for the Healthy Brains Healthy Lives (HBHL) program. S.R. received a scholarship from the Canadian Institutes of Health Research. Z.G.O. is supported by the Fonds de recherche du Quebec Sante (FRQS) Chercheurs boursiers award and is a William Dawson and Killam Scholar. UK Biobank Resources were accessed under application number 45551. 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. The AMP PD program is a public-private partnership managed by the Foundation for the National Institutes of Health and funded by the National Institute of Neurological Disorders and Stroke (NINDS) in partnership with the Aligning Science Across Parkinson's (ASAP) initiative; Celgene Corporation, a subsidiary of Bristol-Myers Squibb Company; GlaxoSmithKline plc (GSK); The Michael J. Fox Foundation for Parkinson's Research; Pfizer Inc.; Sanofi US Services Inc.; and Verily Life Sciences. Clinical data and biosamples used in preparation of this article were obtained from the (i) Michael J. Fox Foundation for Parkinson's Research (MJFF) and National Institutes of Neurological Disorders and Stroke (NINDS) BioFIND study, (ii) Harvard Biomarkers Study (HBS), (iii) NINDS Parkinson's Disease Biomarkers Program (PDBP), (iv) MJFF Parkinson's Progression Markers Initiative (PPMI), and (vii) NINDS Study of Isradipine as a Disease-modifying Agent in Subjects With Early Parkinson Disease, Phase 3 (STEADY-PD3). BioFIND is sponsored by The Michael J. Fox Foundation for Parkinson's Research (MJFF) with support from the National Institute for Neurological Disorders and Stroke (NINDS). The BioFIND Investigators have not participated in reviewing the data analysis or content of the manuscript. For up-to-date information on the study, visit michaeljfox.org/news/biofind. The Harvard Biomarker Study (HBS) is a collaboration of HBS investigators [full list of HBS investigators found at https://www.bwhparkinsoncenter.org/biobank/ and funded through philanthropy and NIH and Non-NIH funding sources. The HBS Investigators have not participated in reviewing the data analysis or content of the manuscript. PPMI is sponsored by The Michael J. Fox Foundation for Parkinson's Research and supported by a consortium of scientific partners: [list the full names of all of the PPMI funding partners found at https://www.ppmi-info.org/about-ppmi/who-we-are/study-sponsors]. The PPMI investigators have not participated in reviewing the data analysis or content of the manuscript. For up-to-date information on the study, visit www.ppmi-info.org. The Parkinson's Disease Biomarker Program (PDBP) consortium is supported by the National Institute of Neurological Disorders and Stroke (NINDS) at the National Institutes of Health. A full list of PDBP investigators can be found at https://pdbp.ninds.nih.gov/policy. The PDBP investigators have not participated in reviewing the data analysis or content of the manuscript. The Study of Isradipine as a Disease-modifying Agent in Subjects With Early Parkinson Disease, Phase 3 (STEADY-PD3) is funded by the National Institute of Neurological Disorders and Stroke (NINDS) at the National Institutes of Health with support from The Michael J. Fox Foundation and the Parkinson Study Group. For additional study information, visit https://clinicaltrials.gov/ct2/show/study/[NCT02168842][1]. The STEADY-PD3 investigators have not participated in reviewing the data analysis or content of the manuscript. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Ethics committee/IRB of McGill University gave ethical approval for this work. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes The data used for this study can be accessed on: FUMA ; Cuomo et al. 2020; Bryois et al. 2021; PPMI ppmi-info.org; UK Biobank , SMR ; and Kamath et al 2021. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT02168842&atom=%2Fmedrxiv%2Fearly%2F2023%2F06%2F27%2F2023.06.20.23291658.atom