During the first hours
after stroke onset neurological deficits can be highly unstable: some
patients rapidly improve, while others deteriorate. This early
neurological instability has a major impact on long-term outcome. Here,
we aimed to determine the genetic architecture of early neurological
instability measured by the difference between NIH stroke scale (NIHSS)
within six hours of stroke onset and NIHSS at 24 h (ΔNIHSS). A total of
5,876 individuals from seven countries (Spain, Finland, Poland, United
States, Costa Rica, Mexico and Korea) were studied using a
multi-ancestry meta-analyses. We found that 8.7% of ΔNIHSS variance was
explained by common genetic variations, and also that early neurological
instability has a different genetic architecture than that of stroke
risk. Eight loci (1p21.1, 1q42.2, 2p25.1, 2q31.2, 2q33.3, 5q33.2,
7p21.2,and 13q31.1) were genome-wide significant and explained 1.8% of
the variability suggesting that additional variants influence early
change in neurological deficits. We used functional genomics and
bioinformatic annotation to identify the genes driving the association
from each loci. eQTL mapping and SMR indicate that ADAM23 (log Bayes Factor (LBF) = 5.41) was driving the association for 2q33.3. Gene based analyses suggested that GRIA1
(LBF = 5.19), which is predominantly expressed in brain, is the gene
driving the association for the 5q33.2 locus. These analyses also
nominated GNPAT (LBF = 7.64)ABCB5 (LBF = 5.97) for the 1p21.1 and 7p21.1 loci. Human brain single nuclei RNA-seq indicates that the gene expression of ADAM23 and GRIA1 is enriched in neurons. ADAM23, a pre-synaptic protein, and GRIA1,
a protein subunit of the AMPA receptor, are part of a synaptic protein
complex that modulates neuronal excitability. These data provides the
first genetic evidence in humans that excitotoxicity may contribute to
early neurological instability after acute ischemic stroke.
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