Cross-Phenotype Meta-Analysis Of Intracerebral Hemorrhageand Small Vessel Ischemic Stroke Identifies Two Novel Genetic Loci At 2q33 And 13q34

Background: Intracerebral hemorrhage (ICH) and small vessel ischemic stroke (SVS) are the most severe manifestation of cerebral small vessel disease (CSVD) with no established preventive approaches beyond hypertension management. Cross-phenotype analysis of these two correlated diseases will improve statistical power to detect novel genetic factors for CSVD, elucidating underlying disease mechanisms that may form the basis for future treatments. Methods: We performed genome-wide association studies (GWAS) for ICH by location in 1,813 ICH patients (797 lobar and 1,005 nonlobar) and 1,711 stroke-free controls after imputation using Haplotype Reference Consortium reference panels. Each ICH GWAS by location was meta-analyzed with GWAS summary statistics for SVS from MEGASTROKE ( Malik et al. 2018 ), using “Multi-Trait Analysis of GWAS” (MTAG; Turley et al. 2018 ) to integrate GWAS summary data across traits and generate combined trait-specific effect estimates. Results: By combining GWAS datasets using MTAG, our functional sample size increased to 241,024 participants (6,255 ICH or SVS cases and 234,769 controls). Genome-wide significant (P < 5x10 -8 ) associations were observed for the nonlobar ICH model enhanced by SVS with 1) rs2758605 (MTAG P-value [P] = 2.6x10 -11 ) at 1q22; 2) rs72932727 (P = 1.7x10 -8 ) at 2q33; and 3) rs9515201 (P = 5.3x10 -10 ) at 13q34. The MTAG association strengths of these loci were at least one order of magnitude more significant than those from their individual GWAS. According to the GTEx database, rs2758605 (1q22), rs72932727 (2q33) and rs9515201 (13q34) are significant cis-eQTLs for PMF1 (P = 1x10 -4 in nerve), NBEAL1 , ICA1L , and CARF (P < 7.7x10 -7 in artery tibial) and COL4A2 and COL4A1 (P < 0.008 in thyroid), respectively. Conclusion: Our cross-phenotype study of ICH and SVS reveals two novel CSVD loci, including 2q33 and 13q34. The 2q33 locus was recently identified in a GWAS of white matter hyperintensity burden ( Jian et al. 2018 ). We also identified the same PMF1 association as previously seen in ICH ( Woo et al. 2014 ), supporting the validity of this novel multi-trait approach. We have begun to replicate these associations and to identify functional causal variants in independent whole genome sequencing studies of ICH.