title: Genome-wide genotyping demonstrates a polygenic risk score associated with white matter hyperintensity volume in CADASIL.
abstract: OBJECTIVE
  White matter hyperintensities (WMH) on MRI are a quantitative marker for sporadic cerebral small vessel disease and are highly heritable. To date, large-scale genetic studies have identified only a single locus influencing WMH burden. This might in part relate to biological heterogeneity of sporadic WMH. The current study searched for genetic modifiers of WMH volume in cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), a monogenic small vessel disease.
  
  
  METHODS
  We performed a genome-wide association study to identify quantitative trait loci for WMH volume by combining data from 517 CADASIL patients collected through 7 centers across Europe. WMH volumes were centrally analyzed and quantified on fluid attenuated inversion recovery images. Genotyping was performed using the Affymetrix 6.0 platform. Individuals were assigned to 2 distinct genetic clusters (cluster 1 and cluster 2) based on their genetic background.
  
  
  RESULTS
  Four hundred sixty-six patients entered the final genome-wide association study analysis. The phenotypic variance of WMH burden in CADASIL explained by all single nucleotide polymorphisms in cluster 1 was 0.85 (SE=0.21), suggesting a substantial genetic contribution. Using cluster 1 as derivation and cluster 2 as a validation sample, a polygenic score was significantly associated with WMH burden (P=0.001) after correction for age, sex, and vascular risk factors. No single nucleotide polymorphism reached genome-wide significance.
  
  
  CONCLUSIONS
  We found a polygenic score to be associated with WMH volume in CADASIL subjects. Our findings suggest that multiple variants with small effects influence WMH burden in CADASIL. The identification of these variants and the biological pathways involved will provide insights into the pathophysiology of white matter disease in CADASIL and possibly small vessel disease in general.
authors.affiliation: From Institute for Stroke and Dementia Research (C.O., M.G., M. Duering, R.M., M. Dichgans), and Department of Neurology (C.O.), Klinikum der Universität München, Ludwig-Maximilians-University, Munich, Germany; Department of Neurology, DHU NeuroVasc, Hopital Lariboisiere, APHP, Paris, France (E.J., H.C.); Université Paris Diderot, Sorbonne Paris Cité, Génétique des Maladies Vasculaires, INSERM UMR-S740, Paris, France (D.H., E.T.-L.); Stroke and Dementia Research Centre, St George's University of London, London, United Kingdom (P.A.-S., S.B.); Neurology Division and Molecular Medicine Section, Mazzoni Hospital, Ascoli Piceno, Italy (L.P., S.S., M.R.); Department of Medicine, Surgery and Neurosciences, University of Siena, Italy (M.T.D., N.D.S., A.F.); Departments of Radiology (M.L.) and Clinical Genetics (E.M.J.B., S.L.O.), Leiden University Medical Center, Leiden, the Netherlands; Stroke Unit and Neurology, Azienda Ospedaliero Universitaria Careggi, Florence, Italy (F.P., L.P.); BioClinica Inc, Lyon, France (C.P., L.B.); Max-Planck Institute of Psychiatry, Munich, Germany (B.M.-M.); Institute of Human Genetics, Helmholtz Center, Munich, Germany (T.M.); Center for Human Genetic Research and Department of Neurology, Massachusetts General Hospital, Boston, MA (N.R., J.R.); Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom (H.S.M.); Program in Medical and Population Genetics, Broad Institute, Cambridge, MA (J.R.); and Munich Cluster for Systems Neurology (SyNergy), Munich, Germany (M. Dichgans).
authors.forename: Christian
authors.initials: C
authors.lastname: Opherk
authors.forename: Mariya
authors.initials: M
authors.lastname: Gonik
authors.forename: Marco
authors.initials: M
authors.lastname: Duering
authors.forename: Rainer
authors.initials: R
authors.lastname: Malik
authors.forename: Eric
authors.initials: E
authors.lastname: Jouvent
authors.forename: Dominique
authors.initials: D
authors.lastname: Hervé
authors.forename: Poneh
authors.initials: P
authors.lastname: Adib-Samii
authors.forename: Steve
authors.initials: S
authors.lastname: Bevan
authors.forename: Luigi
authors.initials: L
authors.lastname: Pianese
authors.forename: Serena
authors.initials: S
authors.lastname: Silvestri
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Dotti
authors.forename: Nicola
authors.initials: N
authors.lastname: De Stefano
authors.forename: Michael
authors.initials: M
authors.lastname: Liem
authors.forename: Elles M J
authors.initials: EM
authors.lastname: Boon
authors.forename: Francesca
authors.initials: F
authors.lastname: Pescini
authors.forename: Chahin
authors.initials: C
authors.lastname: Pachai
authors.forename: Luc
authors.initials: L
authors.lastname: Bracoud
authors.forename: Bertram
authors.initials: B
authors.lastname: Müller-Myhsok
authors.forename: Thomas
authors.initials: T
authors.lastname: Meitinger
authors.forename: Natalia
authors.initials: N
authors.lastname: Rost
authors.forename: Leonardo
authors.initials: L
authors.lastname: Pantoni
authors.forename: Saskia
authors.initials: S
authors.lastname: Lesnik Oberstein
authors.forename: Antonio
authors.initials: A
authors.lastname: Federico
authors.forename: Michele
authors.initials: M
authors.lastname: Ragno
authors.forename: Hugh S
authors.initials: HS
authors.lastname: Markus
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Tournier-Lasserve
authors.forename: Jonathan
authors.initials: J
authors.lastname: Rosand
authors.forename: Hugues
authors.initials: H
authors.lastname: Chabriat
authors.forename: Martin
authors.initials: M
authors.lastname: Dichgans
mesh_terms: D000328:Adult; D000368:Aged; D046589:CADASIL / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology; D005260:Female; D020022:Genetic Predisposition to Disease / Q000453:epidemiology / Q000235:genetics*; D055106:Genome-Wide Association Study; D006801:Humans; D006973:Hypertension / Q000453:epidemiology / Q000235:genetics / Q000473:pathology; D056784:Leukoencephalopathies / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D008957:Models, Genetic; D040641:Quantitative Trait Loci; D012307:Risk Factors
keywords: CADASIL; cerebral small vessel diseases; genetics; genome-wide association study; leukoaraiosis