Abstract 119: Stroke Recovery and Genetic Variation: Main Results of the STRONG Study

Abstract

Introduction: The STRONG (Stroke, sTress, RehabilitatiON, and Genetics) study performed detailed behavioral phenotyping to evaluate genetic variants in relation to stroke recovery and stress responses. Methods: Adults with a new stroke enrolled at 28 US sites were assessed 4 times over 1 year. Three pre-specified gene variants (ApoE-e4, rs6265 (BDNF), & a dopamine polygenic score) were examined for associations with change in grip strength, function (SIS-ADL), mood (PHQ8), and cognition (tMoCA). Seven candidate gene variants (HTTLPR, rs324420, rs4291, rs6265, rs4680, rs53576, rs1360780) were examined for associations with post-stroke trauma, mood, & PTSD. Data were Holm-Bonferroni corrected. Next, genome-wide association studies (GWAS) were performed to identify variants associated with 8 stroke outcomes of interest. Results: The 763 enrollees had age 63.1±14.9 yrs; initial NIHSS score 4 [2-9]; 41.2% Female; 69.4% White. Presence of the BDNF rs6265 polymorphism (in 27.1% of patients) was associated with a 0.9 point reduction in 1 yr tMoCA score (p=10^-5). Two of the 7 stress-related gene candidates [rs4291 (ACE) and rs4680 (COMT)] were risk factors linking increased post-stroke trauma with higher 1yr PHQ8 & PTSD scores (p<0.05). In GWAS, 4 of the 8 behavioral outcomes had significant (p<5x10^-8) associations with genetic variants. Change in grip strength (from acute to d90) had the largest number of genome-wide significant (147 at p<5x10^-8) and suggestive (2,541 at p<5x10^-6) associations; variants with p<5x10^-6 were then mapped to corresponding genes and their protein products to construct an interaction network, which had significant enrichment of protein-protein interactions (283 proteins, 69 edges, p=0.008) and which mapped (FDR<0.05) to multiple gene ontology biological processes pertaining to the nervous system, including nervous system development, neurogenesis, and neuron differentiation. Conclusions: Stroke recovery occurs across many dimensions and so benefits from detailed characterization over time. Building on such assessments, current results from candidate genetic variants and GWAS provide insights into the biology of stroke recovery and inform therapeutic targets for promoting improved stroke recovery.