omicSynth: An open multi-omic community resource for identifying druggable targets across neurodegenerative diseases

• Published in: American journal of human genetics Vol. 111; no. 1; pp. 150 - 164
• Main Authors: Alvarado, Chelsea X., Makarious, Mary B., Weller, Cory A., Vitale, Dan, Koretsky, Mathew J., Bandres-Ciga, Sara, Iwaki, Hirotaka, Levine, Kristin, Singleton, Andrew, Faghri, Faraz, Nalls, Mike A., Leonard, Hampton L.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 04.01.2024; Elsevier
• Subjects: Alzheimer Disease - drug therapy; Alzheimer Disease - genetics; Community Resources; druggability; Humans; Mendelian Randomization Analysis; Multiomics; neurodegeneration; Neurodegenerative Diseases - drug therapy; Neurodegenerative Diseases - genetics; Parkinson Disease; SMR; summary-data-based Mendelian randomization; neurodegeneration; SMR; druggability; summary-data-based Mendelian randomization
• ISSN: 0002-9297; 1537-6605; 1537-6605
• DOI: 10.1016/j.ajhg.2023.12.006

Treatments for neurodegenerative disorders remain rare, but recent FDA approvals, such as lecanemab and aducanumab for Alzheimer disease (MIM: 607822), highlight the importance of the underlying biological mechanisms in driving discovery and creating disease modifying therapies. The global population is aging, driving an urgent need for therapeutics that stop disease progression and eliminate symptoms. In this study, we create an open framework and resource for evidence-based identification of therapeutic targets for neurodegenerative disease. We use summary-data-based Mendelian randomization to identify genetic targets for drug discovery and repurposing. In parallel, we provide mechanistic insights into disease processes and potential network-level consequences of gene-based therapeutics. We identify 116 Alzheimer disease, 3 amyotrophic lateral sclerosis (MIM: 105400), 5 Lewy body dementia (MIM: 127750), 46 Parkinson disease (MIM: 605909), and 9 progressive supranuclear palsy (MIM: 601104) target genes passing multiple test corrections (pSMR_multi < 2.95 × 10−6 and pHEIDI > 0.01). We created a therapeutic scheme to classify our identified target genes into strata based on druggability and approved therapeutics, classifying 41 novel targets, 3 known targets, and 115 difficult targets (of these, 69.8% are expressed in the disease-relevant cell type from single-nucleus experiments). Our novel class of genes provides a springboard for new opportunities in drug discovery, development, and repurposing in the pre-competitive space. In addition, looking at drug-gene interaction networks, we identify previous trials that may require further follow-up such as riluzole in Alzheimer disease. We also provide a user-friendly web platform to help users explore potential therapeutic targets for neurodegenerative diseases, decreasing activation energy for the community. [Display omitted] Neurodegenerative diseases (NDDs) affect millions of people, and finding genetically supported and effective drug targets has been difficult. Omic data availability and statistical methods can help nominate potential drug targets. We identified 54 NDD-related genes for further functional follow up and drug repurposing.