Genome-Wide Association Study of Hematoma Volume Identifies 17p12 as a Novel Susceptibility Locus for Severity and Outcome in Intracerebral Hemorrhage (S1.002)

Objective: We performed a genome-wide association study (GWAS) of ICH volume with the aims of identifying novel biological pathways involved in the pathophysiology of ICH. Background: Hematoma volume is a powerful predictor of clinical outcome in spontaneous intracerebral hemorrhage (ICH). Recent studies indicate that the role of genetic variation extends beyond risk to also influence clinical severity, radiological severity and functional outcome in this condition. Despite these findings, GWAS focused on ICH volume are lacking. Design/Methods: We conducted a two-stage (discovery and replication) cohort study that included ICH patients of European ancestry. We utilized admission head CT to calculate hematoma volume and classify ICH cases as lobar or non-lobar. Seven million genetic variants were available for association testing, which was carried out using linear regression. Signals with p −8 were pursued in replication and tested for association with admission Glasgow Coma Scale (aGCS) and 3-month post-ICH dichotomized (0–2 vs 3–6) modified Rankin Scale (mRS) using ordinal and logistic regression, respectively. Results: The discovery phase included 394 ICH cases (228 lobar and 166 non-lobar) and identified 2 susceptibility loci: a genomic region on 22q13 encompassing PARVB (top SNP rs9614326, beta 1.84, SE 32; p=4.4×10 −8 ) for lobar ICH volume; and an intergenic region on 17p12 (top SNP rs11655160, beta 0.95, SE 17, p=4.3×10 −8 ) for non-lobar ICH volume. The replication included 240 ICH cases (71 lobar and 169 non-lobar) and corroborated the association for 17p12 (p=0.04, meta-analysis p=2.5×10 −9 heterogeneity-p=0.17) but not for 22q13 (p=0.49). In multivariable analysis, rs11655160 was also associated with lower aGCS (OR 0.23, p=0.004) and increased risk of poor 3-month mRS (OR 1.94, p=0.045). Conclusions: We identified 17p12 as a novel susceptibility risk locus for hematoma volume, clinical severity and functional outcome in non-lobar ICH. Replication in other ethnicities and follow-up translational studies are needed to elucidate the mechanism mediating the observed association. Study Supported by: This work was supported by the NIH National Institute of Neurological Disorders and Stroke (K23NS086873, U01NS069763, and R01NS093870). Project support for the GLGC through C.J.W. and S.K. was provided by the NIH National Heart, Lung, and Blood Institute (R01HL127564). Lund Stroke Register has been supported by the Swedish Heart and Lung Foundation, Skane University Hospital, Region Skane, the Freemasons Lodge of Instruction EOS in Lund, King Gustaf V and Queen Victoria’s Foundation, Lund University, the Swedish Stroke Association. Spain studies has been supported by Spain’s Ministry of Health (Ministerio de Sanidad y Consumo, Instituto de Salud Carlos III FEDER, RD12/0042/0020). Drs. Falcone and Brouwers were supported by the NIHNINDS SPOTRIAS fellowship grant P50NS061343. Dr. Anderson was supported by the American Brain Foundation, and received support from the Massachusetts General Hospital Institute for Heart, Vascular, and Stroke Care. Dr. Falcone is a Pepper Scholar with support from the Claude D. Pepper Older Americans Independence Center at Yale School of Medicine (P30AG021342). Disclosure: Dr. Marini has nothing to disclose. Dr. Devan has nothing to disclose. Dr. Radmanesh has nothing to disclose. Dr. Miyares has nothing to disclose. Dr. Poterba has nothing to disclose. Dr. Hansen has nothing to disclose. Dr. Norrving has nothing to disclose. Dr. Giralt-Steinhauer has nothing to disclose. Dr. Jimenez-Conde has nothing to disclose. Dr. Elosua has nothing to disclose. Dr. Cuadrado-Godia has nothing to disclose. Dr. Soriano has nothing to disclose. Dr. Roquer Gonzalez has nothing to disclose. Dr. Kourkoulis has nothing to disclose. Dr. Ayres has nothing to disclose. Dr. Schwab has nothing to disclose. Dr. Tirschwell has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Abbot. Dr. Selim has nothing to disclose. Dr. Brown has nothing to disclose. Dr. Silliman has nothing to disclose. Dr. Worrall has nothing to disclose. Dr. Meschia has nothing to disclose. Dr. Kidwell has nothing to disclose. Dr. Montaner has nothing to disclose. Dr. Fernandez-Cadenas has nothing to disclose. Dr. Delgado has nothing to disclose. Dr. Greenberg has nothing to disclose. Dr. Lindgren has nothing to disclose. Dr. Matouk has nothing to disclose. Dr. Sheth has nothing to disclose. Dr. Woo has nothing to disclose. Dr. Anderson has nothing to disclose. Dr. Rosand has nothing to disclose. Dr Falcone has nothing to disclose.