Pleiotropy analysis between lobar intracerebral hemorrhage and CSF beta-amyloid highlights new and established associations

Background and aims: Combining biologically related traits in genome-wide association studies (GWAS) increases the power for genetic discovery. Given the established relationship between lobar intracerebral hemorrhage (ICH) and cerebral amyloid angiopathy (CAA), and between the latter and levels of cerebrospinal fluid amyloid-beta 42 (CSF-A beta 42), we leveraged genetic predisposition for lower CSF-A beta 42 levels as a proxy phenotype for CAA to identify new genes associated with lobar ICH.Methods: We used publicly available GWAS data for CSF-A beta 42 levels (n = 3146) and for lobar ICH (n = 2094). First, we evaluated the association between lobar ICH risk and CSF-A beta 42 in lobar ICH patients using a polygenic risk score (PRS) for CSF-A beta 42. Next, we conducted multi-trait analysis of GWAS (MTAG) for pleiotropy analysis of lobar ICH and CSF-A beta 42. MTAG results were further tested using Expression Quantitative Trait Locus and Differential Gene Expression Analyses.Results: CSF-A beta 42 PRS was associated with lobar ICH risk (p = 0.04). MTAG analysis identified a novel association within CDH9 (rs1007589; minor allele frequency = 0.09; MTAG p = 5.4 x 10(-8); lobar ICH odds ratio = 1.4 and p = 2.4 x 10(-3); CSF-A beta 42 beta = -0.03 and p = 4.5 x 10(-6)). rs1007589 was significantly associated with the expression levels of CDH9 in temporal and occipital cortices, regions known to preferentially accumulate microhemorrhages in CAA.Conclusion: Our pleiotropy analysis suggested a variant possibly implicated with lobar ICH driven by amyloid-related mechanisms in CDH9 and associated with differential expression in brain regions characteristically affected by CAA. CDH9 is one subtype of the cadherin superfamily, which regulates intercellular adhesion, is involved in blood-brain barrier integrity, and is elevated in Alzheimer's disease patients. Further analyses are warranted to understand the effects of the variant on the pathogenesis of ICH and its clinical significance.