Genome-wide association study of cerebral small vessel disease reveals established and novel loci

Research output: Contribution to journalArticle

Abstract

Intracerebral haemorrhage and small vessel ischaemic stroke (SVS) are the most acute manifestations of cerebral small vessel disease, with no established preventive approaches beyond hypertension management. Combined genome-wide association study (GWAS) of these two correlated diseases may improve statistical power to detect novel genetic factors for cerebral small vessel disease, elucidating underlying disease mechanisms that may form the basis for future treatments. Because intracerebral haemorrhage location is an adequate surrogate for distinct histopathological variants of cerebral small vessel disease (lobar for cerebral amyloid angiopathy and non-lobar for arteriolosclerosis), we performed GWAS of intracerebral haemorrhage by location in 1813 subjects (755 lobar and 1005 non-lobar) and 1711 stroke-free control subjects. Intracerebral haemorrhage GWAS results by location were meta-analysed with GWAS results for SVS from MEGASTROKE, using 'Multi-Trait Analysis of GWAS' (MTAG) to integrate summary data across traits and generate combined effect estimates. After combining intracerebral haemorrhage and SVS datasets, our sample size included 241 024 participants (6255 intracerebral haemorrhage or SVS cases and 233 058 control subjects). Genome-wide significant associations were observed for non-lobar intracerebral haemorrhage enhanced by SVS with rs2758605 [MTAG P-value (P) = 2.6 × 10-8] at 1q22; rs72932727 (P = 1.7 × 10-8) at 2q33; and rs9515201 (P = 5.3 × 10-10) at 13q34. In the GTEx gene expression library, rs2758605 (1q22), rs72932727 (2q33) and rs9515201 (13q34) are significant cis-eQTLs for PMF1 (P = 1 × 10-4 in tibial nerve), NBEAL1, FAM117B and CARF (P < 2.1 × 10-7 in arteries) and COL4A2 and COL4A1 (P < 0.01 in brain putamen), respectively. Leveraging S-PrediXcan for gene-based association testing with the predicted expression models in tissues related with nerve, artery, and non-lobar brain, we found that experiment-wide significant (P < 8.5 × 10-7) associations at three genes at 2q33 including NBEAL1, FAM117B and WDR12 and genome-wide significant associations at two genes including ICA1L at 2q33 and ZCCHC14 at 16q24. Brain cell-type specific expression profiling libraries reveal that SEMA4A, SLC25A44 and PMF1 at 1q22 and COL4A1 and COL4A2 at 13q34 were mainly expressed in endothelial cells, while the genes at 2q33 (FAM117B, CARF and NBEAL1) were expressed in various cell types including astrocytes, oligodendrocytes and neurons. Our cross-phenotype genetic study of intracerebral haemorrhage and SVS demonstrates novel genome-wide associations for non-lobar intracerebral haemorrhage at 2q33 and 13q34. Our replication of the 1q22 locus previous seen in traditional GWAS of intracerebral haemorrhage, as well as the rediscovery of 13q34, which had previously been reported in candidate gene studies with other cerebral small vessel disease-related traits strengthens the credibility of applying this novel genome-wide approach across intracerebral haemorrhage and SVS.

Details

Authors
  • Jaeyoon Chung
  • Sandro Marini
  • Joanna Pera
  • Bo Norrving
  • Jordi Jimenez-Conde
  • Jaume Roquer
  • Israel Fernandez-Cadenas
  • David L. Tirschwell
  • Magdy Selim
  • Devin L. Brown
  • Scott L. Silliman
  • Bradford B. Worrall
  • James F. Meschia
  • Stacie Demel
  • Steven M. Greenberg
  • Agnieszka Slowik
  • Arne Lindgren
  • Reinhold Schmidt
  • Matthew Traylor
  • Muralidharan Sargurupremraj
  • Steffen Tiedt
  • Rainer Malik
  • Stéphanie Debette
  • Martin Dichgans
  • Carl D. Langefeld
  • Daniel Woo
  • Jonathan Rosand
  • Christopher D. Anderson
  • International Stroke Genetics Consortium
Organisations
External organisations
  • Massachusetts General Hospital
  • Broad Institute
  • Jagellonian University
  • Skåne University Hospital
  • Autonomous University of Barcelona
  • Hospital de Sant Pau
  • University of Washington
  • Beth Israel Deaconess Medical Center
  • University of Michigan
  • University of Florida
  • University of Virginia Health System
  • Mayo Clinic Minnesota
  • Medical University of Graz
  • University of Cambridge
  • Centre Hospitalier Universitaire de Bordeaux
  • German Center for Neurodegenerative Diseases (DZNE), Bonn
  • Vall d'Hebron University Hospital
  • University of Cincinnati
  • University of Bordeaux
  • Munich Cluster for Systems Neurology
  • Ludwig-Maximilian University of Munich
  • Wake Forest University
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Medical Genetics
  • Neurology

Keywords

  • cerebral small vessel disease, genome-wide association studies, multi-trait analysis
Original languageEnglish
Pages (from-to)3176-3189
Number of pages14
JournalBrain : a journal of neurology
Volume142
Issue number10
Publication statusPublished - 2019
Publication categoryResearch
Peer-reviewedYes