Multi-ancestry GWAS reveals excitotoxicity associated with outcome after ischaemic stroke

Abstract

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.

Nanomaterials alleviating redox stress in neurological diseases: mechanisms and applications

“…Ancestry is a fixed characteristic of the genome. It influences the pathology and symptomatology of diseases by determining the genetic architecture [ 172 , 176 ]. NMs administered to subjects with different ancestral backgrounds may yield different results.…”

Genome-Wide Studies in Ischaemic Stroke: Are Genetics Only Useful for Finding Genes?

“…The GWAS studies may allow us to uncover genes and pathways that shape the dynamic processes involved in stroke outcomes from early brain injury to long-term recovery. Despite the high number of genetic risk loci associated with stroke risk (>30 loci) [ 7 ], only a few have been associated with stroke outcome [ 21 , 22 , 23 ], thus suggesting that genetic factors related to stroke outcome are likely to be different from those influencing stroke risk. In addition, it has been observed that early neurological change after stroke measured using ΔNIHSS24 h (the difference between the NIHSS score at 24 h and the NIHSS score at baseline (less than 6 h from stroke onset)), has a different genetic architecture than the risk of IS [ 24 ].…”

“…The GENISIS (Genetics of Early Instability After Ischaemic Stroke) study performed a GWAS with 5876 individuals to examine neurological evolution in the acute phase of stroke using ΔNIHSS24 h. This study showed that common genetic variants accounted for 8.7% of the variance in ΔNIHSS24 h. The authors identified eight genome-wide significant loci associated with ΔNIHSS24 h ( Figure 1 ) [ 23 ]. These results explained only 1.8% of the variance in ΔNIHSS24 h. However, they also found that excitotoxicity could play an important role in neurological deterioration after stroke.…”

Grand challenges in stroke genomics

“…The change in National Institutes of Health Stroke Scale (NIHSS) during the first 24 h post stroke ( NIHSS 24h ) has been used as a measure of evolution of neurological deficits in the acute phase. A GWAS of NIHSS 24h has identified 7 genetic loci that harbor genes influencing excitotoxicity (Ibanez et al, 2022). Neuroimaging endophenotypes that capture hemorrhagic transformation or edema formation are also of great interest.…”