The following is a summary of “Identification of Genetic Loci Associated With Intracerebral Hemorrhage Using a Multitrait Analysis Approach,” published in the September 2024 issue of Neurology by Muiño et al.
Researchers conducted a retrospective study to discover new loci through multi-trait analysis of GWAS [MTAG] and explore gene-based analyses (transcriptome-wide association study (TWAS), and proteome-wide association study (PWAS) to understand the biological mechanisms of spontaneous ICH and identify potential therapeutic targets.
They used the published MTAG for ICH in 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’s disease (AD). Researchers assembled traits with a genetic correlation ≥0.3 for analysis. A new MTAG was performed with traits whose pairwise MTAG yielded new GWAS-significant single nucleotide polymorphisms (SNPs), with a posterior probability of model 3 (GWAS-pairwise) ≥0.6—conducted TWAS and PWAS to correlate genetic components of expression or protein levels with genetic components of traits, using the cohort of ICH from the UK Biobank for replication.
The results showed that for all ICH (1,543 ICH, 1,711 controls), the mean age was 72 ± 2 in cases and 70 ± 2 in controls, and half were women. The replication cohort included 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. The study replicated 6 SNPs belonging to 2q33.2 (ICA1L, β = 0.20, SE = 0.03, P=8.91 × 10-12), 10q24.33 (OBFC1, β = −0.12, SE = 0.02, P=1.67 × 10-8), 13q34 (COL4A2, β = 0.02, SE = 0.02, P=2.34 × 10-11), and 19q13.32 (APOC1, β = −0.19, SE = 0.03, P=1.38 × 10-12; APOE, β = 0.21, SE = 0.03, P=2.70 × 10-11; PVRL2:CTB-129P6.4, β = 0.15, SE = 0.03, P=1.38 × 10-8); 2 genes (SH3PXD2A, Z-score = 4.83, P=6.67 × 10-7; and APOC1, Z-score: = 5.11, P=1.60 × 10-7); and ICA1L transcript (Z-score = 6.8, P=9.1 × 10-12) and protein levels (Z-score = −5.8, P=6.7 × 10-9).
They concluded that results reinforced the role of APOE in ICH risk, replicated previous ICH-associated loci, and identified new ICH associations while acknowledging the limitation of using data from European subjects.
Source: neurology.org/doi/10.1212/WNL.0000000000209666
