title: Genetic risk load according to the site of intracranial aneurysms.
abstract: OBJECTIVE
  We investigated whether risk alleles of single nucleotide polymorphisms associated with intracranial aneurysm (IA) are enriched in patients with familial IA, IA located at the middle cerebral artery (MCA), or IA rupture at a younger age.
  
  
  METHODS
  In this case-only study, we calculated genetic risk scores (GRS) for 973 Dutch and 718 Finnish patients with IA by summing effect size-weighted risk allele counts of 7 single nucleotide polymorphisms associated with IAs previously identified through genome-wide association studies. We tested the GRS for association with presence of familial IA or IA at the MCA using logistic regression, and with age at time of IA rupture using linear regression. We also calculated odds ratios with 95% confidence intervals for the proportion of patients with each characteristic in the highest compared with the lowest GRS tertile.
  
  
  RESULTS
  GRS were higher in IA at the MCA in the Dutch (p = 2.5 × 10(-4)), Finnish (p = 0.039), and combined cohort (p = 4.9 × 10(-5)). GRS were not associated with familial IA in the Dutch (p = 0.34), Finnish (p = 0.45), and combined cohort (p = 0.98), or with age at time of IA rupture in the Dutch (p = 0.28), Finnish (p = 0.86), and combined cohort (p = 0.45). In the combined cohort, odds ratios were 0.89 (0.67-1.20) for familial IA, 1.03 (0.79-1.34) for lower age, and 1.54 (1.20-1.98) for MCA aneurysms.
  
  
  CONCLUSIONS
  Our findings suggest that genetic risk factors have a larger role in the development of IA at the MCA than at other sites, and that genetic heterogeneity should be considered in future genetic studies.
authors.affiliation: From the Utrecht Stroke Center, Department of Neurology and Neurosurgery, Rudolf Magnus Institute of Neuroscience (F.N.G.v.t.H., R. Kleinloog, G.J.E.R., Y.M.R.), and Departments of Epidemiology (P.I.W.d.B.) and Medical Genetics (P.I.W.d.B.), University Medical Center Utrecht, the Netherlands; Neurosurgery of NeuroCenter (M.I.K., M.v.u.z.F., J.E.J.), Kuopio University Hospital; Public Health Genomics Unit (E.I.G., A.L.), Department of Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki; Institute for Molecular Medicine Finland (E.I.G.), University of Helsinki; Department of Neurosurgery (E.I.G., H.L., R. Kivisaari, M.N., J.H.), Helsinki University Central Hospital, Finland; and Department of Neurology (M.C.B., D.v.d.B.), Center of Infection and Immunity Amsterdam, Academic Medical Center, Amsterdam, the Netherlands. f.vanthof@umcutrecht.nl.
authors.forename: Femke N G
authors.initials: FN
authors.lastname: van 't Hof
authors.affiliation: From the Utrecht Stroke Center, Department of Neurology and Neurosurgery, Rudolf Magnus Institute of Neuroscience (F.N.G.v.t.H., R. Kleinloog, G.J.E.R., Y.M.R.), and Departments of Epidemiology (P.I.W.d.B.) and Medical Genetics (P.I.W.d.B.), University Medical Center Utrecht, the Netherlands; Neurosurgery of NeuroCenter (M.I.K., M.v.u.z.F., J.E.J.), Kuopio University Hospital; Public Health Genomics Unit (E.I.G., A.L.), Department of Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki; Institute for Molecular Medicine Finland (E.I.G.), University of Helsinki; Department of Neurosurgery (E.I.G., H.L., R. Kivisaari, M.N., J.H.), Helsinki University Central Hospital, Finland; and Department of Neurology (M.C.B., D.v.d.B.), Center of Infection and Immunity Amsterdam, Academic Medical Center, Amsterdam, the Netherlands.
authors.forename: Mitja I
authors.initials: MI
authors.lastname: Kurki
authors.affiliation: From the Utrecht Stroke Center, Department of Neurology and Neurosurgery, Rudolf Magnus Institute of Neuroscience (F.N.G.v.t.H., R. Kleinloog, G.J.E.R., Y.M.R.), and Departments of Epidemiology (P.I.W.d.B.) and Medical Genetics (P.I.W.d.B.), University Medical Center Utrecht, the Netherlands; Neurosurgery of NeuroCenter (M.I.K., M.v.u.z.F., J.E.J.), Kuopio University Hospital; Public Health Genomics Unit (E.I.G., A.L.), Department of Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki; Institute for Molecular Medicine Finland (E.I.G.), University of Helsinki; Department of Neurosurgery (E.I.G., H.L., R. Kivisaari, M.N., J.H.), Helsinki University Central Hospital, Finland; and Department of Neurology (M.C.B., D.v.d.B.), Center of Infection and Immunity Amsterdam, Academic Medical Center, Amsterdam, the Netherlands.
authors.forename: Rachel
authors.initials: R
authors.lastname: Kleinloog
authors.affiliation: From the Utrecht Stroke Center, Department of Neurology and Neurosurgery, Rudolf Magnus Institute of Neuroscience (F.N.G.v.t.H., R. Kleinloog, G.J.E.R., Y.M.R.), and Departments of Epidemiology (P.I.W.d.B.) and Medical Genetics (P.I.W.d.B.), University Medical Center Utrecht, the Netherlands; Neurosurgery of NeuroCenter (M.I.K., M.v.u.z.F., J.E.J.), Kuopio University Hospital; Public Health Genomics Unit (E.I.G., A.L.), Department of Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki; Institute for Molecular Medicine Finland (E.I.G.), University of Helsinki; Department of Neurosurgery (E.I.G., H.L., R. Kivisaari, M.N., J.H.), Helsinki University Central Hospital, Finland; and Department of Neurology (M.C.B., D.v.d.B.), Center of Infection and Immunity Amsterdam, Academic Medical Center, Amsterdam, the Netherlands.
authors.forename: Paul I W
authors.initials: PI
authors.lastname: de Bakker
authors.affiliation: From the Utrecht Stroke Center, Department of Neurology and Neurosurgery, Rudolf Magnus Institute of Neuroscience (F.N.G.v.t.H., R. Kleinloog, G.J.E.R., Y.M.R.), and Departments of Epidemiology (P.I.W.d.B.) and Medical Genetics (P.I.W.d.B.), University Medical Center Utrecht, the Netherlands; Neurosurgery of NeuroCenter (M.I.K., M.v.u.z.F., J.E.J.), Kuopio University Hospital; Public Health Genomics Unit (E.I.G., A.L.), Department of Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki; Institute for Molecular Medicine Finland (E.I.G.), University of Helsinki; Department of Neurosurgery (E.I.G., H.L., R. Kivisaari, M.N., J.H.), Helsinki University Central Hospital, Finland; and Department of Neurology (M.C.B., D.v.d.B.), Center of Infection and Immunity Amsterdam, Academic Medical Center, Amsterdam, the Netherlands.
authors.forename: Mikael
authors.initials: M
authors.lastname: von und zu Fraunberg
authors.affiliation: From the Utrecht Stroke Center, Department of Neurology and Neurosurgery, Rudolf Magnus Institute of Neuroscience (F.N.G.v.t.H., R. Kleinloog, G.J.E.R., Y.M.R.), and Departments of Epidemiology (P.I.W.d.B.) and Medical Genetics (P.I.W.d.B.), University Medical Center Utrecht, the Netherlands; Neurosurgery of NeuroCenter (M.I.K., M.v.u.z.F., J.E.J.), Kuopio University Hospital; Public Health Genomics Unit (E.I.G., A.L.), Department of Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki; Institute for Molecular Medicine Finland (E.I.G.), University of Helsinki; Department of Neurosurgery (E.I.G., H.L., R. Kivisaari, M.N., J.H.), Helsinki University Central Hospital, Finland; and Department of Neurology (M.C.B., D.v.d.B.), Center of Infection and Immunity Amsterdam, Academic Medical Center, Amsterdam, the Netherlands.
authors.forename: Juha E
authors.initials: JE
authors.lastname: Jääskeläinen
authors.affiliation: From the Utrecht Stroke Center, Department of Neurology and Neurosurgery, Rudolf Magnus Institute of Neuroscience (F.N.G.v.t.H., R. Kleinloog, G.J.E.R., Y.M.R.), and Departments of Epidemiology (P.I.W.d.B.) and Medical Genetics (P.I.W.d.B.), University Medical Center Utrecht, the Netherlands; Neurosurgery of NeuroCenter (M.I.K., M.v.u.z.F., J.E.J.), Kuopio University Hospital; Public Health Genomics Unit (E.I.G., A.L.), Department of Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki; Institute for Molecular Medicine Finland (E.I.G.), University of Helsinki; Department of Neurosurgery (E.I.G., H.L., R. Kivisaari, M.N., J.H.), Helsinki University Central Hospital, Finland; and Department of Neurology (M.C.B., D.v.d.B.), Center of Infection and Immunity Amsterdam, Academic Medical Center, Amsterdam, the Netherlands.
authors.forename: Emília I
authors.initials: EI
authors.lastname: Gaál
authors.affiliation: From the Utrecht Stroke Center, Department of Neurology and Neurosurgery, Rudolf Magnus Institute of Neuroscience (F.N.G.v.t.H., R. Kleinloog, G.J.E.R., Y.M.R.), and Departments of Epidemiology (P.I.W.d.B.) and Medical Genetics (P.I.W.d.B.), University Medical Center Utrecht, the Netherlands; Neurosurgery of NeuroCenter (M.I.K., M.v.u.z.F., J.E.J.), Kuopio University Hospital; Public Health Genomics Unit (E.I.G., A.L.), Department of Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki; Institute for Molecular Medicine Finland (E.I.G.), University of Helsinki; Department of Neurosurgery (E.I.G., H.L., R. Kivisaari, M.N., J.H.), Helsinki University Central Hospital, Finland; and Department of Neurology (M.C.B., D.v.d.B.), Center of Infection and Immunity Amsterdam, Academic Medical Center, Amsterdam, the Netherlands.
authors.forename: Hanna
authors.initials: H
authors.lastname: Lehto
authors.affiliation: From the Utrecht Stroke Center, Department of Neurology and Neurosurgery, Rudolf Magnus Institute of Neuroscience (F.N.G.v.t.H., R. Kleinloog, G.J.E.R., Y.M.R.), and Departments of Epidemiology (P.I.W.d.B.) and Medical Genetics (P.I.W.d.B.), University Medical Center Utrecht, the Netherlands; Neurosurgery of NeuroCenter (M.I.K., M.v.u.z.F., J.E.J.), Kuopio University Hospital; Public Health Genomics Unit (E.I.G., A.L.), Department of Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki; Institute for Molecular Medicine Finland (E.I.G.), University of Helsinki; Department of Neurosurgery (E.I.G., H.L., R. Kivisaari, M.N., J.H.), Helsinki University Central Hospital, Finland; and Department of Neurology (M.C.B., D.v.d.B.), Center of Infection and Immunity Amsterdam, Academic Medical Center, Amsterdam, the Netherlands.
authors.forename: Riku
authors.initials: R
authors.lastname: Kivisaari
authors.affiliation: From the Utrecht Stroke Center, Department of Neurology and Neurosurgery, Rudolf Magnus Institute of Neuroscience (F.N.G.v.t.H., R. Kleinloog, G.J.E.R., Y.M.R.), and Departments of Epidemiology (P.I.W.d.B.) and Medical Genetics (P.I.W.d.B.), University Medical Center Utrecht, the Netherlands; Neurosurgery of NeuroCenter (M.I.K., M.v.u.z.F., J.E.J.), Kuopio University Hospital; Public Health Genomics Unit (E.I.G., A.L.), Department of Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki; Institute for Molecular Medicine Finland (E.I.G.), University of Helsinki; Department of Neurosurgery (E.I.G., H.L., R. Kivisaari, M.N., J.H.), Helsinki University Central Hospital, Finland; and Department of Neurology (M.C.B., D.v.d.B.), Center of Infection and Immunity Amsterdam, Academic Medical Center, Amsterdam, the Netherlands.
authors.forename: Aki
authors.initials: A
authors.lastname: Laakso
authors.affiliation: From the Utrecht Stroke Center, Department of Neurology and Neurosurgery, Rudolf Magnus Institute of Neuroscience (F.N.G.v.t.H., R. Kleinloog, G.J.E.R., Y.M.R.), and Departments of Epidemiology (P.I.W.d.B.) and Medical Genetics (P.I.W.d.B.), University Medical Center Utrecht, the Netherlands; Neurosurgery of NeuroCenter (M.I.K., M.v.u.z.F., J.E.J.), Kuopio University Hospital; Public Health Genomics Unit (E.I.G., A.L.), Department of Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki; Institute for Molecular Medicine Finland (E.I.G.), University of Helsinki; Department of Neurosurgery (E.I.G., H.L., R. Kivisaari, M.N., J.H.), Helsinki University Central Hospital, Finland; and Department of Neurology (M.C.B., D.v.d.B.), Center of Infection and Immunity Amsterdam, Academic Medical Center, Amsterdam, the Netherlands.
authors.forename: Mika
authors.initials: M
authors.lastname: Niemelä
authors.affiliation: From the Utrecht Stroke Center, Department of Neurology and Neurosurgery, Rudolf Magnus Institute of Neuroscience (F.N.G.v.t.H., R. Kleinloog, G.J.E.R., Y.M.R.), and Departments of Epidemiology (P.I.W.d.B.) and Medical Genetics (P.I.W.d.B.), University Medical Center Utrecht, the Netherlands; Neurosurgery of NeuroCenter (M.I.K., M.v.u.z.F., J.E.J.), Kuopio University Hospital; Public Health Genomics Unit (E.I.G., A.L.), Department of Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki; Institute for Molecular Medicine Finland (E.I.G.), University of Helsinki; Department of Neurosurgery (E.I.G., H.L., R. Kivisaari, M.N., J.H.), Helsinki University Central Hospital, Finland; and Department of Neurology (M.C.B., D.v.d.B.), Center of Infection and Immunity Amsterdam, Academic Medical Center, Amsterdam, the Netherlands.
authors.forename: Juha
authors.initials: J
authors.lastname: Hernesniemi
authors.affiliation: From the Utrecht Stroke Center, Department of Neurology and Neurosurgery, Rudolf Magnus Institute of Neuroscience (F.N.G.v.t.H., R. Kleinloog, G.J.E.R., Y.M.R.), and Departments of Epidemiology (P.I.W.d.B.) and Medical Genetics (P.I.W.d.B.), University Medical Center Utrecht, the Netherlands; Neurosurgery of NeuroCenter (M.I.K., M.v.u.z.F., J.E.J.), Kuopio University Hospital; Public Health Genomics Unit (E.I.G., A.L.), Department of Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki; Institute for Molecular Medicine Finland (E.I.G.), University of Helsinki; Department of Neurosurgery (E.I.G., H.L., R. Kivisaari, M.N., J.H.), Helsinki University Central Hospital, Finland; and Department of Neurology (M.C.B., D.v.d.B.), Center of Infection and Immunity Amsterdam, Academic Medical Center, Amsterdam, the Netherlands.
authors.forename: Matthijs C
authors.initials: MC
authors.lastname: Brouwer
authors.affiliation: From the Utrecht Stroke Center, Department of Neurology and Neurosurgery, Rudolf Magnus Institute of Neuroscience (F.N.G.v.t.H., R. Kleinloog, G.J.E.R., Y.M.R.), and Departments of Epidemiology (P.I.W.d.B.) and Medical Genetics (P.I.W.d.B.), University Medical Center Utrecht, the Netherlands; Neurosurgery of NeuroCenter (M.I.K., M.v.u.z.F., J.E.J.), Kuopio University Hospital; Public Health Genomics Unit (E.I.G., A.L.), Department of Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki; Institute for Molecular Medicine Finland (E.I.G.), University of Helsinki; Department of Neurosurgery (E.I.G., H.L., R. Kivisaari, M.N., J.H.), Helsinki University Central Hospital, Finland; and Department of Neurology (M.C.B., D.v.d.B.), Center of Infection and Immunity Amsterdam, Academic Medical Center, Amsterdam, the Netherlands.
authors.forename: Diederik
authors.initials: D
authors.lastname: van de Beek
authors.affiliation: From the Utrecht Stroke Center, Department of Neurology and Neurosurgery, Rudolf Magnus Institute of Neuroscience (F.N.G.v.t.H., R. Kleinloog, G.J.E.R., Y.M.R.), and Departments of Epidemiology (P.I.W.d.B.) and Medical Genetics (P.I.W.d.B.), University Medical Center Utrecht, the Netherlands; Neurosurgery of NeuroCenter (M.I.K., M.v.u.z.F., J.E.J.), Kuopio University Hospital; Public Health Genomics Unit (E.I.G., A.L.), Department of Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki; Institute for Molecular Medicine Finland (E.I.G.), University of Helsinki; Department of Neurosurgery (E.I.G., H.L., R. Kivisaari, M.N., J.H.), Helsinki University Central Hospital, Finland; and Department of Neurology (M.C.B., D.v.d.B.), Center of Infection and Immunity Amsterdam, Academic Medical Center, Amsterdam, the Netherlands.
authors.forename: Gabriël J E
authors.initials: GJ
authors.lastname: Rinkel
authors.affiliation: From the Utrecht Stroke Center, Department of Neurology and Neurosurgery, Rudolf Magnus Institute of Neuroscience (F.N.G.v.t.H., R. Kleinloog, G.J.E.R., Y.M.R.), and Departments of Epidemiology (P.I.W.d.B.) and Medical Genetics (P.I.W.d.B.), University Medical Center Utrecht, the Netherlands; Neurosurgery of NeuroCenter (M.I.K., M.v.u.z.F., J.E.J.), Kuopio University Hospital; Public Health Genomics Unit (E.I.G., A.L.), Department of Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki; Institute for Molecular Medicine Finland (E.I.G.), University of Helsinki; Department of Neurosurgery (E.I.G., H.L., R. Kivisaari, M.N., J.H.), Helsinki University Central Hospital, Finland; and Department of Neurology (M.C.B., D.v.d.B.), Center of Infection and Immunity Amsterdam, Academic Medical Center, Amsterdam, the Netherlands.
authors.forename: Ynte M
authors.initials: YM
authors.lastname: Ruigrok
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002648:Child; D015331:Cohort Studies; D005260:Female; D005387:Finland; D005787:Gene Frequency; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D002532:Intracranial Aneurysm / Q000235:genetics*; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D009426:Netherlands; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D055815:Young Adult