Abstract Body: Background: Stroke is a major cause of long-term disability and has widely varying recovery outcomes. While clinical factors like stroke severity play a role, genetic factors are increasingly recognized as important contributors to stroke recovery. This study aims to identify genetic variants associated with recovery phenotypes through genome-wide association studies (GWAS) and protein-protein interaction (PPI) networks.
Methods: DNA from STRONG study participants was genotyped using the Infinium Global Screening Array, resulting in 565 samples and 9,814,610 variants after quality control. GWAS were conducted on 11 recovery phenotypes using plink v1.9, including motor (Grip Strength), cognition (tMoCA), functional performance (SIS-ADL), mental health (PHQ-8 and PTSD), and disability (mRS). Models adjusted for age, sex, stroke severity acutely, and ancestry. To further examine how the identified genetic variants may relate to biological mechanisms of recovery, PPI networks and gene ontology enrichment analyses were conducted.
Results: Participants’ stroke severity was mild to moderate (acute NIHSS median score 4, IQR 2 – 9). Several cross-phenotype associations were identified for genes of biological interest: Grip strength, PHQ8, and PTSD were associated with the rs138829971-C variant near DCLK2 (involved in hippocampal organization). Grip strength and tMoCA were associated with the rs149456987-T variant near UNK (crucial for cortical neuron development). The PPI networks for multiple phenotypes (including SIS ADL and mRS at 3 months, change in Grip Strength from 1-3 months, PHQ8 and PTSD measures at 12 months) were significantly enriched in protein-protein interactions, and for GO terms including Nervous System Development (SIS ADL), Post-synaptic Density (PHQ8), Neuron Projection (tMOCA) and Axon Guidance (Grip Strength).
Conclusions: While some genetic variations affect specific domains of recovery, others have cross-phenotype associations that affect recovery more broadly. Our analyses identified several gene associations and biological pathways active during development, suggesting a potential shared biology with reparative processes post-stroke. Other associated genes affecting axon guidance that we identified remain expressed in adult brain tissue and could offer targets for developing drug therapies.