PII-048 - GENOME-WIDE ASSOCIATION STUDY OF CENTRAL NERVOUS SYSTEM MEDICATION-INDUCED ADVERSE DRUG REACTIONS AMONG A SUBSET OF PARTICIPANTS IN THE NIH ALL OF US RESEARCH PROGRAM

O. AlAzzeh¹, J. McClay²; ¹Virginia Commonwealth University School of Pharmacy, Richmond, VA, USA, ²Virginia Commonwealth University School of Pharmacy, Richmond, USA, USA.

Background: Diverse factors influence risk for adverse drug reactions (ADRs), with central nervous system (CNS) drug-induced reactions among those most frequently reported to the FDA. Drug-induced dizziness, a common ADR of gabapentin affecting up to 30% of users, poses significant risks to safety and quality of life, particularly among older adults. This study aims to map genetic polymorphisms associated with gabapentin-induced dizziness utilizing the NIH All of Us (AoU) Research Program dataset.

Methods: We conducted a GWAS using AoU's Controlled Tier Dataset v7 on the Researcher Workbench cloud environment. Adult participants who met our inclusion and exclusion criteria were selected via the cohort builder tool, based on exposure to gabapentin (RxNorm: 25480). Case status was assigned based on the occurrence of dizziness (SNOMED CT: 271789005) within 90 days of initiating treatment. Using Hail, we imported genomic data from the Global Diversity Array, applying standard GWAS quality control including a minor allele frequency filter of >0.01. Logistic regression analysis was executed with a cohort of 35,950 subjects adjusting for multiple covariates including concurrent diseases, sex and top ancestry principal components.

Results: Our GWAS analyzed 970,648 variants in a sample of 3,510 dizziness cases and 32,440 controls. We identified several variants with suggestive associations with gabapentin-induced dizziness, although none reached genome-wide significance (p-value < 5 × 10-8). The top findings include: rs1433943 at MCTP2 gene (p = 5.64 x 10-7), rs542043596 at GAS2 gene (p = 1.48 × 10- 6), rs56148079 at PTPRO gene (p = 1.91 x 10-6), rs73065460 at RERG gene (p = 2.63 x 10-6), and rs79783031 at ANKS1B gene (p = 3.48 x 10-6). The QQ plot revealed no systematic bias (λ =1.02).

Conclusion: This study revealed multiple potential genetic variants associated with gabapentin-induced dizziness, including the MCTP2 gene (Multiple C2 And Transmembrane Domain Containing 2) which encodes a protein involved in neurotransmitter regulation. MCTP2 was previously associated with risk for motion sickness via GWAS. However, none of the variants had a large effect on risk for dizziness. Subsequent studies employing larger study populations are needed to validate and extend our results.