Deep Resequencing of the 1q22 Locus in Non-lobar Intracerebral Hemorrhage

Objective: Genome-wide association studies have identified as a susceptibility locus for cerebral small vessel diseases (CSVDs), including non-lobar intracerebral hemorrhage (ICH) and lacunar stroke. In the present study we performed targeted high-depth sequencing of in ICH cases and controls to further characterize this locus and prioritize potential causal mechanisms, which remain unknown.

Methods: 95,000 base pairs spanning , including and / were sequenced in 1,055 spontaneous ICH cases (534 lobar and 521 non-lobar) and 1,078 controls. Firth regression and RIFT analysis were used to analyze common and rare variants, respectively. Chromatin interaction analyses were performed using Hi-C, ChIP-Seq and ChIA-PET databases. Multivariable Mendelian randomization (MVMR) assessed whether alterations in gene-specific expression relative to regionally co-expressed genes at could be causally related to ICH risk.

Results: Common and rare variant analyses prioritized variants in 5'-UTR and intronic regions, overlapping with active promoter and enhancer regions based on ENCODE annotation. Hi-C data analysis determined that is spatially organized in a single chromatin loop and that the genes therein belong to the same Topologically Associating Domain. ChIP-Seq and ChIA-PET data analysis highlighted the presence of long-range interactions between the -promoter and -enhancer regions prioritized by association testing. MVMR analyses demonstrated that overexpression could be causally related to non-lobar ICH risk.

Interpretation: Altered promoter-enhancer interactions leading to overexpression, potentially dysregulating polyamine catabolism, could explain demonstrated associations with non-lobar ICH risk at , offering a potential new target for prevention of ICH and CSVD.