title: Heritability estimates identify a substantial genetic contribution to risk and outcome of intracerebral hemorrhage.
abstract: OBJECTIVE
  Previous studies suggest that genetic variation plays a substantial role in occurrence and evolution of intracerebral hemorrhage (ICH). Genetic contribution to disease can be determined by calculating heritability using family-based data, but such an approach is impractical for ICH because of lack of large pedigree-based studies. However, a novel analytic tool based on genome-wide data allows heritability estimation from unrelated subjects. We sought to apply this method to provide heritability estimates for ICH risk, severity, and outcome.
  
  
  METHODS
  We analyzed genome-wide genotype data for 791 ICH cases and 876 controls, and determined heritability as the proportion of variation in phenotype attributable to captured genetic variants. Contribution to heritability was separately estimated for the APOE (encoding apolipoprotein E) gene, an established genetic risk factor, and for the rest of the genome. Analyzed phenotypes included ICH risk, admission hematoma volume, and 90-day mortality.
  
  
  RESULTS
  ICH risk heritability was estimated at 29% (SE, 11%) for non-APOE loci and at 15% (SE, 10%) for APOE. Heritability for 90-day ICH mortality was 41% for non-APOE loci and 10% (SE, 9%) for APOE. Genetic influence on hematoma volume was also substantial: admission volume heritability was estimated at 60% (SE, 70%) for non-APOEloci and at 12% (SE, 4%) for APOE.
  
  
  CONCLUSIONS
  Genetic variation plays a substantial role in ICH risk, outcome, and hematoma volume. Previously reported risk variants account for only a portion of inherited genetic influence on ICH pathophysiology, pointing to additional loci yet to be identified.
authors.affiliation: Center for Human Genetic Research, Massachusetts General Hospital, 185 Cambridge St, CPZN-6818, Boston, MA 02114, USA.
authors.forename: William J
authors.initials: WJ
authors.lastname: Devan
authors.forename: Guido J
authors.initials: GJ
authors.lastname: Falcone
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Anderson
authors.forename: Jeremiasz M
authors.initials: JM
authors.lastname: Jagiella
authors.forename: Helena
authors.initials: H
authors.lastname: Schmidt
authors.forename: Björn M
authors.initials: BM
authors.lastname: Hansen
authors.forename: Jordi
authors.initials: J
authors.lastname: Jimenez-Conde
authors.forename: Eva
authors.initials: E
authors.lastname: Giralt-Steinhauer
authors.forename: Elisa
authors.initials: E
authors.lastname: Cuadrado-Godia
authors.forename: Carolina
authors.initials: C
authors.lastname: Soriano
authors.forename: Alison M
authors.initials: AM
authors.lastname: Ayres
authors.forename: Kristin
authors.initials: K
authors.lastname: Schwab
authors.forename: Sylvia Baedorf
authors.initials: SB
authors.lastname: Kassis
authors.forename: Valerie
authors.initials: V
authors.lastname: Valant
authors.forename: Joanna
authors.initials: J
authors.lastname: Pera
authors.forename: Andrzej
authors.initials: A
authors.lastname: Urbanik
authors.forename: Anand
authors.initials: A
authors.lastname: Viswanathan
authors.forename: Natalia S
authors.initials: NS
authors.lastname: Rost
authors.forename: Joshua N
authors.initials: JN
authors.lastname: Goldstein
authors.forename: Paul
authors.initials: P
authors.lastname: Freudenberger
authors.forename: Eva-Maria
authors.initials: EM
authors.lastname: Stögerer
authors.forename: Bo
authors.initials: B
authors.lastname: Norrving
authors.forename: David L
authors.initials: DL
authors.lastname: Tirschwell
authors.forename: Magdy
authors.initials: M
authors.lastname: Selim
authors.forename: Devin L
authors.initials: DL
authors.lastname: Brown
authors.forename: Scott L
authors.initials: SL
authors.lastname: Silliman
authors.forename: Bradford B
authors.initials: BB
authors.lastname: Worrall
authors.forename: James F
authors.initials: JF
authors.lastname: Meschia
authors.forename: Chelsea S
authors.initials: CS
authors.lastname: Kidwell
authors.forename: Joan
authors.initials: J
authors.lastname: Montaner
authors.forename: Israel
authors.initials: I
authors.lastname: Fernandez-Cadenas
authors.forename: Pilar
authors.initials: P
authors.lastname: Delgado
authors.forename: Steven M
authors.initials: SM
authors.lastname: Greenberg
authors.forename: Jaume
authors.initials: J
authors.lastname: Roquer
authors.forename: Arne
authors.initials: A
authors.lastname: Lindgren
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Slowik
authors.forename: Reinhold
authors.initials: R
authors.lastname: Schmidt
authors.forename: Daniel
authors.initials: D
authors.lastname: Woo
authors.forename: Jonathan
authors.initials: J
authors.lastname: Rosand
authors.forename: Alessandro
authors.initials: A
authors.lastname: Biffi
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001057:Apolipoproteins E / Q000235:genetics; D016022:Case-Control Studies; D002543:Cerebral Hemorrhage / Q000175:diagnosis* / Q000235:genetics* / Q000401:mortality; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D014644:Genetic Variation / Q000235:genetics*; D055106:Genome-Wide Association Study; D005838:Genotype; D006406:Hematoma / Q000235:genetics / Q000473:pathology; D006801:Humans; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D011379:Prognosis; D012307:Risk Factors; D012720:Severity of Illness Index; D015996:Survival Rate
chemical_list: D001057:Apolipoproteins E
keywords: common genetic variants; genes; genetics; heritability; intracerebral hemorrhage; stroke
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