Genetic Variation and Stroke Recovery: The STRONG Study
Authors: Cramer Steven C. , Parodi Livia , Moslemi Zahra , Braun Robynne G. , Aldridge Chad M. , Shahbaba Babak , Rosand Jonathan , Holman E. Alison , Shah Shreyansh , Griessenauer Christoph J. , Patel Nirav , Anderson Christopher , Henry Jonathan , Kourkoulis Christina , Lin David J. , Zaba Natalie , Gee Joey , Moon Johnson , Schwertfeger Julie , Jayaraman Arun , Lee Robert , Lansberg Maarten G. , Kemp Stephanie , Huang Emily , Bingham Elijah , Lugo Leonel , Eun Da Eun (Katie) , Payne Jeremy , Patten Carolynn , Ng Kwan , Cao Madelyn , Jubb Ashley , McGee Breann , Shahbaba Ryan , Agrawal Kunal , Kissela Brett , DeJong Stacey , Cole John , Silver Brian , Manxhari Christina , Cucchiara Brett , Busza Ania , Hepple Jennifer Paige , Liew Sook-Lei , Alderman Susan , Beauchamp Jennifer , Mathew Nitha Joseph , Hayes Heather , Majersik Jennifer J. , Worrall Bradford B. , Tirschwell David , Bushnell Cheryl , Husseini Nada El , Lee Jin-Moo , Falcone Guido J. 
Published: July 2024

BACKGROUND:
Genetic association studies can reveal biology and treatment targets but have received limited attention for stroke recovery. STRONG (Stroke, Stress, Rehabilitation, and Genetics) was a prospective, longitudinal (1-year), genetic study in adults with stroke at 28 US stroke centers. The primary aim was to examine the association that candidate genetic variants have with (1) motor/functional outcomes and (2) stress-related outcomes.

METHODS:
For motor/functional end points, 3 candidate gene variants (ApoE ε4, BDNF [brain-derived neurotrophic factor], and a dopamine polygenic score) were analyzed for associations with change in grip strength (3 months-baseline), function (3-month Stroke Impact Scale-Activities of Daily Living), mood (3-month Patient Health Questionnaire-8), and cognition (12-month telephone-Montreal Cognitive Assessment). For stress-related outcomes, 7 variants (serotonin transporter gene–linked promoter region, ACE [angiotensin-converting enzyme], oxytocin receptor, FKBP5 [FKBP prolyl isomerase 5], FAAH [fatty acid amide hydrolase], BDNF, and COMT [catechol-O-methyltransferase]) were assessed for associations with posttraumatic stress disorder ([PTSD]; PTSD Primary Care Scale) and depression (Patient Health Questionnaire-8) at 6 and 12 months; stress-related genes were examined as a function of poststroke stress level. Statistical models (linear, negative binomial, or Poisson regression) were based on response variable distribution; all included stroke severity, age, sex, and ancestry as covariates. Stroke subtype was explored secondarily. Data were Holm-Bonferroni corrected. A secondary replication analysis tested whether the rs1842681 polymorphism (identified in the GISCOME study [Genetics of Ischaemic Stroke Functional Outcome]) was related to 3-month modified Rankin Scale score in STRONG.

RESULTS:

The 763 enrollees were 63.1±14.9 (mean±SD) years of age, with a median initial National Institutes of Health Stroke Scale score of 4 (interquartile range, 2–9); outcome data were available in n=515 at 3 months, n=500 at 6 months, and n=489 at 12 months. At 1 year poststroke, the rs6265 (BDNF) variant was associated with poorer cognition (0.9-point lower telephone-Montreal Cognitive Assessment score,
P
=1×10
−5
). For stress-related outcomes, rs4291 (ACE) and rs324420 (FAAH) were risk factors linking increased poststroke stress with higher 1-year depression and PTSD symptoms (
P
<0.05), while rs4680 (COMT) linked poststroke stress with lower 1-year depression and PTSD. Findings were unchanged when considering stroke subtype. STRONG replicated GISCOME: rs1842681 was associated with lower 3-month modified Rankin Scale score (
P
=3.2×10
−5
).

CONCLUSIONS:
This study identified genetic associations with cognitive function, depression, and PTSD 1 year poststroke. Genetic susceptibility to PTSD and depressive symptoms varied according to the amount of poststroke stress, underscoring the critical role of lived experiences in recovery. Together, the results suggest that genetic association studies provide insights into the biology of stroke recovery in humans.