Publicaciones

Sex Differences in Frequency, Severity, and Distribution of Cerebral Microbleeds

Fandler-Höfler S, Eppinger S, Ambler G et al. JAMA Netw Open. 2024 Oct 1;7(10):e2439571. doi: 10.1001/jamanetworkopen.2024.39571. PMID: 39405058

https://pubmed.ncbi.nlm.nih.gov/39405058/

Background and Objectives: Genome-wide association studies (GWASs) have only 2 loci associated with spontaneous intracerebral hemorrhage (ICH): APOE for lobar and 1q22 for nonlobar ICH. We aimed to discover new loci through an analysis that combines correlated traits (multi-trait analysis of GWAS [MTAG]) and explore a gene-based analysis, transcriptome-wide association study (TWAS), and proteome-wide association study (PWAS) to understand the biological mechanisms of spontaneous ICH providing potential therapeutic targets.

Methods: Weuse the published MTAG of ICH (patients with spontaneous intraparenchymal bleeding) and small-vessel ischemic stroke. For all ICH, lobar ICH, and nonlobar ICH, a pairwise MTAG combined ICH with traits related to cardiovascular risk factors, cerebrovascular diseases, or Alzheimer disease (AD). For the analysis, we assembled those traits with a genetic correlation ≥0.3. A new MTAGcombining multiple traits was performed with those traits whose pairwise MTAG yielded new GWAS-significant single nucleotide polymorphisms (SNPs), with a posterior-probability of model 3 (GWAS-pairwise) ≥0.6. We perform TWAS and PWAS that correlate the genetic component ofexpression or proteinlevels withthe genetic componen to fa trait. We use the ICH cohort from UK Biobank as replication.

Results: For all ICH (1,543 ICH, 1,711 controls), the mean age was 72 ± 2 in cases and 70 ± 2 in controls, and half of them were women. Replication cohort: 700 ICH and 399,717 controls. Novel loci were found only for all ICH (the trait containing lobar and nonlobar ICH), combining data of ICH and small vessel stroke, white matter hyperintensities volume, fractional anisotropy, mean diffusivity, and AD. We replicated 6 SNPs belonging to 2q33.2 (ICA1L, β = 0.20, SE = 0.03, p value = 8.91 × 10−12), 10q24.33 (OBFC1, β = −0.12, SE =0.02, p value = 1.67 ×10−8), 13q34 (COL4A2, β = 0.02, SE = 0.02, p value = 2.34 × 10−11), and 19q13.32 (APOC1, β =−0.19, SE =0.03, p value = 1.38 × 10−12; APOE, β = 0.21, SE = 0.03, p value = 2.70 × 10−11; PVRL2:CTB-129P6.4, β = 0.15, SE = 0.03, p value = 1.38 × 10−8); 2 genes (SH3PXD2A, Zscore = 4.83, p value = 6.67 × 10−7;andAPOC1, Z-score: = 5.11, p value = 1.60 × 10−7); and ICA1L transcript (Z-score = 6.8, p value = 9.1 × 10−12) and protein levels (Z-score = −5.8, p value = 6.7 × 10−9).

Funding: This work was supported by grants from the Institutode Salud CarlosIII (PI11/0176),Generaci´on Project,Maestro Project (PI18/01338), INVICTUS+ network, RICORSICTUS (RD21/0006/0006) together with Next-Generation EU funds that finance the actions of the Recovery and Resilience Mechanism,and the Epigenesis Project (Marat´ode TV3), FEDER funds, iBio Stroke project (AC19/00106).E. Muiño is supportedby a R´ıoHortega Contract (CM18/00198) from the Instituto de Salud Carlos III. E. Muiño is supported by the Juan Rod´es contract (JR23/00045) from Instituto de Salud Carlos III. C. Gallego-Fabrega is supported by a Sara Borrell Contract (CD20/00043) from Instituto de Salud Carlos III and Fondo Europeo de Desarrollo Regional (ISCIII-FEDER). M. Lled´os is supported by a PFIS Contract (Contratos Predoctorales de Formaci´on en Investigaci´on en Salud) from the Instituto de Salud Carlos III (FI19/00309). I. Fern´andez-Cadenas (CP12/03298) is supported by a research contract from Miguel Servet Program from the Instituto de Salud Carlos III.

 

Sex-Stratified Genome-Wide Association Study in the Spanish Population Identifies a Novel Locus for Lacunar Stroke

Cárcel-Márquez J, Muiño E, Gallego-Fabrega C et al. Stroke. 2024 Oct;55(10):2462-2471. doi: 10.1161/STROKEAHA.124.047833. Epub 2024 Sep 24 .PMID: 39315829.

https://pubmed.ncbi.nlm.nih.gov/39315829/

Background: Ischemic stroke (IS) represents a significant health burden globally, necessitating a better understanding of its genetic underpinnings to improve prevention and treatment strategies. Despite advances in IS genetics, studies focusing on the Spanish population and sex-stratified analyses are lacking.

Methods: A case-control genome-wide association study was conducted with 9081 individuals (3493 IS cases and 5588 healthy controls). IS subtypes using Trial of ORG 10172 in Acute Stroke Treatment criteria were explored in a sex-stratified approach. Replication efforts involved the MEGASTROKE, GIGASTROKE, and the UK Biobank international cohorts. Post-genome-wide association study analysis included: in silico proteomic analysis, gene-based analysis, quantitative trait loci annotation, transcriptome-wide association analysis, and bioinformatic analysis using chromatin accessibility data.

Results: Identified as associated with IS and its subtypes were 4 significant and independent loci. Replication confirmed 5p15.2 as a new locus associated with small-vessel occlusion stroke, with rs59970332-T as the lead variant (beta [SE], 0.13 [0.02]; P=4.34×10−8). Functional analyses revealed CTNND2 given proximity and its implication in pathways involved in vascular integrity and angiogenesis. Integration of Hi-C data identified additional potentially modulated genes, and in silico proteomic analysis suggested a distinctive blood proteome profile associated with the lead variant. Gene-set enrichment analyses highlighted pathways consistent with small-vessel disease pathogenesis. Gene-based associations with known stroke-related genes such as F2 and FGG were also observed, reinforcing the relevance of our findings.

Conclusions: We found CTNND2 as a potential key molecule in small-vessel occlusion stroke risk, and predominantly in males. This study sheds light on the genetic architecture of IS in the Spanish population, providing novel insights into sex-specific associations and potential molecular mechanisms. Further research, including replication in larger cohorts, is essential for a comprehensive understanding of these findings and for their translation to clinical practice.

Funding: This study has been funded by Instituto de Salud Carlos III (grant numbers PI18/01338, PI20/00925, PMP21/00165, and PI21/01088), Network of European Funding for Neuroscience Research (AC19/00106), RICORS-ICTUS: Red de Investigación Cooperativa Orientada a Resultados en Salud – Enfermedades Vasculares Cerebrales (RD21/0006/0006), Centro de Investigación Biomédica en Red en Enfermedades Neurodegenerativas (CB22/05/00067), Fondo Europeo de Desarrollo Regional, NextGeneration EU, Centres de Recerca de Catalunya Programme/Generalitat de Catalunya, Marató de 3cat grant numbers: 202306-30, 202310-30 and National Institutes of Health RO1 grant Genetic Architecture of Cerebral Edema after Stroke.