17p12 Influences Hematoma Volume and Outcome in Spontaneous Intracerebral Hemorrhage

Sandro Marini; William J Devan; Farid Radmanesh; Laura Miyares; Timothy Poterba; Björn M Hansen; Bo Norrving; Jordi Jimenez-Conde; Eva Giralt-Steinhauer; Roberto Elosua; Elisa Cuadrado-Godia; Carolina Soriano; Jaume Roquer; Christina E Kourkoulis; Alison M Ayres; Kristin Schwab; David L Tirschwell; Magdy Selim; Devin L Brown; Scott L Silliman; Bradford B Worrall; James F Meschia; Chelsea S Kidwell; Joan Montaner; Israel Fernandez-Cadenas; Pilar Delgado; Steven M Greenberg; Arne Lindgren; Charles Matouk; Kevin N Sheth; Daniel Woo; Christopher D Anderson; Jonathan Rosand; Guido J Falcone; International Stroke Genetics Consortium

doi:10.1161/STROKEAHA.117.020091

17p12 Influences Hematoma Volume and Outcome in Spontaneous Intracerebral Hemorrhage

Stroke. 2018 Jul;49(7):1618-1625. doi: 10.1161/STROKEAHA.117.020091. Epub 2018 Jun 18.

Authors

Sandro Marini¹, William J Devan¹, Farid Radmanesh¹, Laura Miyares², Timothy Poterba³, Björn M Hansen^{4

5

6}, Bo Norrving^{4

5

6}, Jordi Jimenez-Conde⁷, Eva Giralt-Steinhauer⁷, Roberto Elosua⁷, Elisa Cuadrado-Godia⁷, Carolina Soriano⁷, Jaume Roquer⁷, Christina E Kourkoulis¹, Alison M Ayres⁸, Kristin Schwab⁸, David L Tirschwell⁹, Magdy Selim¹⁰, Devin L Brown¹¹, Scott L Silliman¹², Bradford B Worrall¹³, James F Meschia¹⁴, Chelsea S Kidwell¹⁵, Joan Montaner¹⁶, Israel Fernandez-Cadenas^{16

17}, Pilar Delgado¹⁶, Steven M Greenberg⁸, Arne Lindgren^{4

5

6}, Charles Matouk², Kevin N Sheth², Daniel Woo¹⁸, Christopher D Anderson^{1

19

20}, Jonathan Rosand^{1

19

20}, Guido J Falcone²¹; International Stroke Genetics Consortium

Affiliations

¹ From the Center for Genomic Medicine (S.M., W.J.D., F.R., C.E.K., C.D.A., J.R.).
² Massachusetts General Hospital, Boston; Division of Neurocritical Care and Emergency Neurology, Department of Neurology, Yale University School of Medicine, New Haven, CT (L.M., C.M., K.N.S., G.J.F.).
³ Analytic and Translational Genetics Unit (T.P.).
⁴ Department of Neurology and Rehabilitation, Skåne University Hospital, Lund, Sweden (B.M.H., B.N., A.L.).
⁵ Department of Clinical Sciences Lund, Neurology, Lund University, Sweden (B.M.H., B.N., A.L.).
⁶ Department of Neurology and Rehabilitation Medicine, Skåne University Hospital, Lund, Sweden (B.M.H., B.N., A.L.).
⁷ Department of Neurology, Hospital del Mar Medical Research Institute (IMIM) (J.J.-C., E.G.-S., R.E., E.C.-G., C.S., J.R.).
⁸ Universitat Autónoma de Barcelona, Spain; Department of Neurology, J. Philip Kistler Stroke Research Center, Massachusetts General Hospital, Boston, MA (A.M.A., K.S., S.M.G.).
⁹ Stroke Center, Harborview Medical Center, University of Washington, Seattle (D.L.T.).
¹⁰ Stroke Division, Department of Neurology, Beth Israel Deaconess Medical Center, Boston, MA (M.S.).
¹¹ Stroke Program, Department of Neurology, University of Michigan, Ann Arbor (D.L.B.).
¹² Department of Neurology, University of Florida College of Medicine, Jacksonville (S.L.S.).
¹³ Department of Neurology and Public Health Sciences, University of Virginia Health System, Charlottesville (B.B.W.).
¹⁴ Department of Neurology, Mayo Clinic, Jacksonville, FL (J.F.M.).
¹⁵ Department of Neurology, University of Arizona, Tucson (C.S.K.).
¹⁶ Neurovascular Research Laboratory and Neurovascular Unit, Institut de Recerca, Hospital Vall d'Hebron (J.M., I.F.-C., P.D.).
¹⁷ Stroke Pharmacogenomics and Genetics Sant Pau Institute of Research, Barcelona, Spain (I.F.-C.).
¹⁸ Department of Neurology and Rehabilitation Medicine, University of Cincinnati College of Medicine, OH (D.W.).
¹⁹ Division of Neurocritical Care and Emergency Neurology, Massachusetts General Hospital, Boston (C.D.A., J.R.).
²⁰ Program in Medical and Population Genetics, Broad Institute, Boston (C.D.A., J.R).
²¹ Massachusetts General Hospital, Boston; Division of Neurocritical Care and Emergency Neurology, Department of Neurology, Yale University School of Medicine, New Haven, CT (L.M., C.M., K.N.S., G.J.F.) guido.falcone@yale.edu.

Abstract

Background and purpose: Hematoma volume is an important determinant of clinical outcome in spontaneous intracerebral hemorrhage (ICH). We performed a genome-wide association study (GWAS) of hematoma volume with the aim of identifying novel biological pathways involved in the pathophysiology of primary brain injury in ICH.

Methods: We conducted a 2-stage (discovery and replication) case-only genome-wide association study in patients with ICH of European ancestry. We utilized the admission head computed tomography to calculate hematoma volume via semiautomated computer-assisted technique. After quality control and imputation, 7 million genetic variants were available for association testing with ICH volume, which was performed separately in lobar and nonlobar ICH cases using linear regression. Signals with P<5×10^-⁸ were pursued in replication and tested for association with admission Glasgow coma scale and 3-month post-ICH dichotomized (0-2 versus 3-6) modified Rankin Scale using ordinal and logistic regression, respectively.

Results: The discovery phase included 394 ICH cases (228 lobar and 166 nonlobar) and identified 2 susceptibility loci: a genomic region on 22q13 encompassing PARVB (top single-nucleotide polymorphism rs9614326: β, 1.84; SE, 0.32; P=4.4×10^-8) for lobar ICH volume and an intergenic region overlying numerous copy number variants on 17p12 (top single-nucleotide polymorphism rs11655160: β, 0.95; SE, 0.17; P=4.3×10^-8) for nonlobar ICH volume. The replication included 240 ICH cases (71 lobar and 169 nonlobar) and corroborated the association for 17p12 (P=0.04; meta-analysis P=2.5×10^-9; heterogeneity, P=0.16) but not for 22q13 (P=0.49). In multivariable analysis, rs11655160 was also associated with lower admission Glasgow coma scale (odds ratio, 0.17; P=0.004) and increased risk of poor 3-month modified Rankin Scale (odds ratio, 1.94; P=0.045).

Conclusions: We identified 17p12 as a novel susceptibility risk locus for hematoma volume, clinical severity, and functional outcome in nonlobar ICH. Replication in other ethnicities and follow-up translational studies are needed to elucidate the mechanism mediating the observed association.

Keywords: cerebral hemorrhage; genetics; genome-wide association study; humans; neuroimaging.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Aged
Aged, 80 and over
Cerebral Hemorrhage / genetics*
Chromosomes, Human, Pair 17*
Female
Genome-Wide Association Study
Genotype
Hematoma / genetics*
Humans
Male
Middle Aged
Polymorphism, Single Nucleotide

Abstract

Publication types

MeSH terms

Grants and funding