Two recent studies, led by researchers from the Sant Pau Research Institute (IR Sant Pau) and conducted in collaboration with hospitals across Spain, have identified significant genetic loci, or DNA regions, associated with lacunar stroke and spontaneous intracerebral hemorrhage. These discoveries open new possibilities for the development of personalized therapies and underscore the importance of genetics in risk stratification for these severe cerebrovascular diseases.
The first study, published in Stroke and led by Dr. Jara Cárcel Márquez and Dr. Israel Fernández-Cadenas from the Pharmacogenomics and Neurovascular Genetics Group at IR Sant Pau, focused on lacunar stroke, a subtype of ischemic stroke caused by the occlusion of small cerebral vessels. This study, the first comprehensive genomic analysis conducted on the Spanish population, highlighted the importance of the CTNND2 gene in the risk of lacunar stroke, particularly in men.
Researchers analyzed data from 9,081 individuals, including 3,493 ischemic stroke cases and 5,588 healthy controls, and validated their findings with international consortia such as MEGASTROKE, GIGASTROKE, and the UK Biobank. One of the most noteworthy discoveries was the identification of locus 5p15.2, with the rs59970332-T variant being the main one associated with lacunar stroke. The CTNND2 gene, located near this locus, may play a crucial role in vascular health and the formation of new blood vessels. Additionally, associations were found with other stroke-related genes, such as F2 and FGG.
This genetic study on the Spanish population has confirmed risk variants in 12 known genes associated with stroke in other international populations, which is essential for the application of precision medicine in Spain. Dr. Cárcel emphasizes that these findings “can help us identify individuals at higher risk of stroke, enabling the implementation of targeted preventive measures in the future.” According to the researchers, this study represents a significant advance in understanding the genetic basis of ischemic stroke and highlights the need to consider sex differences in genetic research.
The second study, published in Neurology and also from the IR Sant Pau group, led by Dr. Elena Muiño and Dr. Israel Fernández-Cadenas, investigated spontaneous intracerebral hemorrhage (ICH), a serious condition affecting 30 out of every 100,000 people globally each year. Using an innovative approach, the study uncovered genetic variants associated with this disease that had previously gone undetected in traditional studies.
The key innovation was a meta-analysis integrating genetic data from various diseases associated with intracerebral hemorrhage, such as vascular conditions, rather than limiting the scope to genetic variants exclusively tied to cerebral hemorrhage. This approach increased statistical power, leading to the detection of four genetic loci associated with ICH that had not been identified before.
Until now, GWAS studies had identified only two main loci associated with ICH: APOE for lobar hemorrhage and locus 1q22 for non-lobar hemorrhage. However, by analyzing data from 1,543 patients with ICH, alongside five related phenotypes and a replication cohort of 399,717 individuals from the UK Biobank, the research team identified several new genetic loci, including OBFC1 (10q24.33), NECTIN2 and APOC1 (19q13.32), and the SH3PXD2A gene, now linked to ICH risk. Additionally, loci ICA1L (2q33.2) and COL4A2 (13q34), previously described, were replicated for the first time.
“This approach allowed us to identify several new genetic loci, including those associated with biological processes like amyloid protein deposition or lipid metabolism, which could be promising therapeutic targets to reduce intracerebral hemorrhage risk in genetically predisposed individuals,” explains Dr. Muiño.
The study employed bioinformatics tools like TWAS (Transcriptome-Wide Association Studies) and PWAS (Protein-Wide Association Studies), enabling a deeper understanding of the underlying biology of ICH by examining the relationship between genetic variants and protein or transcript expression.
“This is a significant step forward in understanding the genetic basis of intracerebral hemorrhage,” notes Dr. Muiño. “The identification of these loci not only provides critical insight into the underlying biological mechanisms but could also point to new therapeutic targets to reduce the risk of ICH in the future and aid decision-making in complex patients.”
The study lays the groundwork for future research, including the use of methods like Mendelian randomization to explore whether the proteins associated with the discovered loci, beyond being associated with hemorrhage, are causal factors in this condition.
The lacunar stroke study was funded by the Instituto de Salud Carlos III, ERA-NET NEURON, the Cooperative Health Research Network on Vascular Diseases, the Center for Biomedical Research in Neurodegenerative Diseases (CIBERNED), European Union Next Generation funds, the CERCA program from the Generalitat de Catalunya, the Marató de 3cat, and the National Institutes of Health (NIH).
The intracerebral hemorrhage study received funding from the Instituto de Salud Carlos III, the Generación Project, the Maestro Project, the INVICTUS+ network, and European Union Next Generation funds. Both studies were made possible through collaboration with multiple hospitals in Spain and international consortia.
Cárcel-Márquez, J. et al. (2024) “Sex-stratified genome-wide association study in the Spanish population identifies a novel locus for lacunar stroke”, Stroke; a journal of cerebral circulation, 55(10), pp. 2462–2471. Disponible en: https://doi.org/10.1161/STROKEAHA.124.047833
Muiño, E. et al. (2024) “Identification of genetic loci associated with intracerebral hemorrhage using a multitrait analysis approach”, Neurology, 103(8), p. e209666. Disponible en: https://doi.org/10.1212/WNL.0000000000209666
