Identification of Genetic Loci Associated With Intracerebral Hemorrhage Using a Multitrait Analysis Approach

Abstract

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: We use 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 MTAG combining 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 of expression or protein levels with the genetic component of a 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, Z-score = 4.83, p value = 6.67 × 10^-7; and APOC1, 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).

Discussion: Our results reinforce the role of APOE in ICH risk, replicate previous ICH-associated loci (2q33 and 13q34), and point to new ICH associations with OBFC1, PVRL2:CTB-129P6.4, APOC1, and SH3PXD2A. Our study used data from European subjects, our main limitation. These molecules could be potential targets for future studies for modulating ICH risk.

Figure 1. Manhattan Plot of the MTAG Performed Here for All ICH-SVS, White Matter Hyperintensities Volume, Fractional Anysotropy, Mean Diffusivity, and Alzheimer Disease

GWAS = genome-wide association study; ICH = intracerebral hemorrhage; MTAG = Multi-Trait Analysis of GWAS; SVS = small-vessel stroke.

Figure 2. Gene-Based Analysis of the MTAG of All ICH-SVS, White Matter Hyperintensities Volume, Fractional Anysotropy, Mean Diffusivity, and Alzheimer Disease

GWAS = genome-wide association study; ICH = intracerebral hemorrhage; MTAG = Multi-Trait Analysis of GWAS; SVS = small-vessel stroke.