Genome-wide association study of cerebral small vessel disease reveals established and novel loci
Por:
Chung, J, Marini, S, Pera, J, Norrving, B, Jimenez-Conde, J, Roquer, J, Fernandez-Cadenas, I, Tirschwell, DL, Selim, M, Brown, DL, Silliman, SL, Worrall, BB, Meschia, JF, Demel, S, Greenberg, SM, Slowik, A, Lindgren, A, Schmidt, R, Traylor, M, Sargurupremraj, M, Tiedt, S, Malik, R, Debette, S, Dichgans, M, Langefeld, CD, Woo, D, Rosand, J, Anderson, CD, Int Stroke Genetics Consortium
Publicada:
1 oct 2019
Resumen:
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 x 10(-8)] at 1q22; rs72932727 (P = 1.7 x 10(-8)) at 2q33; and rs9515201 (P = 5.3 x 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 x 10(-4) in tibial nerve), NBEAL1, FAM117B and CARF (P<2.1 x 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 x 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.
Filiaciones:
Chung, J:
Massachusetts Gen Hosp, Ctr Genom Med, Boston, MA 02114 USA
Broad Inst, Program Med & Populat Genet, Cambridge, MA USA
Marini, S:
Massachusetts Gen Hosp, Ctr Genom Med, Boston, MA 02114 USA
Broad Inst, Program Med & Populat Genet, Cambridge, MA USA
Pera, J:
Jagiellonian Univ, Coll Med, Dept Neurol, Krakow, Poland
Norrving, B:
Lund Univ, Dept Clin Sci Lund, Neurol, Lund, Sweden
Skane Univ Hosp, Dept Neurol & Rehabil Med, Lund, Sweden
Jimenez-Conde, J:
Univ Autonoma Barcelona, Inst Hosp del Mar Invest Med, Dept Neurol, Neurovasc Res Unit, Barcelona, Spain
Roquer, J:
Univ Autonoma Barcelona, Inst Hosp del Mar Invest Med, Dept Neurol, Neurovasc Res Unit, Barcelona, Spain
Fernandez-Cadenas, I:
Univ Autonoma Barcelona, Neurovasc Res Lab, Barcelona, Spain
Univ Autonoma Barcelona, Hosp Vall dHebron, Inst Recerca, Neurovasc Unit, Barcelona, Spain
Hosp Santa Creu & Sant Pau, St Pau Inst Res, Stroke Pharmacogen & Genet, Barcelona, Spain
Tirschwell, DL:
Univ Washington, Harborview Med Ctr, Stroke Ctr, 325 9th Ave, Seattle, WA 98104 USA
Selim, M:
Beth Israel Deaconess Med Ctr, Dept Neurol, Stroke Div, Boston, MA 02215 USA
Brown, DL:
Univ Michigan, Dept Neurol, Stroke Program, Ann Arbor, MI USA
Silliman, SL:
Univ Florida, Coll Med, Dept Neurol, Jacksonville, FL USA
Worrall, BB:
Univ Virginia Hlth Syst, Dept Neurol & Publ Hlth Sci, Charlottesville, VA USA
Meschia, JF:
Mayo Clin, Dept Neurol, Jacksonville, FL 32224 USA
Demel, S:
Univ Cincinnati, Coll Med, Dept Neurol & Rehabil Med, Cincinnati, OH USA
Greenberg, SM:
Massachusetts Gen Hosp, J Philip Kistler Stroke Res Ctr, Boston, MA 02114 USA
Slowik, A:
Jagiellonian Univ, Coll Med, Dept Neurol, Krakow, Poland
Lindgren, A:
Lund Univ, Dept Clin Sci Lund, Neurol, Lund, Sweden
Skane Univ Hosp, Dept Neurol & Rehabil Med, Lund, Sweden
Schmidt, R:
Med Univ Graz, Dept Neurol, Graz, Austria
Traylor, M:
Univ Cambridge, Dept Clin Neurosci, Cambridge, England
Sargurupremraj, M:
Univ Bordeaux, INSERM, U1219, Bordeaux Populat Hlth Res Ctr, Bordeaux, France
Tiedt, S:
Ludwig Maximilians Univ Munchen, Univ Hosp, Inst Stroke & Dementia Res, Munich, Germany
Munich Cluster Syst Neurol SyNergy, Munich, Germany
Malik, R:
Ludwig Maximilians Univ Munchen, Univ Hosp, Inst Stroke & Dementia Res, Munich, Germany
Munich Cluster Syst Neurol SyNergy, Munich, Germany
Debette, S:
Univ Bordeaux, INSERM, U1219, Bordeaux Populat Hlth Res Ctr, Bordeaux, France
Univ Bordeaux, Bordeaux Univ Hosp, Memory Clin, Dept Neurol, Bordeaux, France
Dichgans, M:
Ludwig Maximilians Univ Munchen, Univ Hosp, Inst Stroke & Dementia Res, Munich, Germany
Munich Cluster Syst Neurol SyNergy, Munich, Germany
German Ctr Neurodegenerat Dis DZNE, Munich, Germany
Langefeld, CD:
Wake Forest Sch Med, Ctr Publ Hlth Genom, Winston Salem, NC 27101 USA
Wake Forest Sch Med, Dept Biostat Sci, Winston Salem, NC 27101 USA
Woo, D:
Mayo Clin, Dept Neurol, Jacksonville, FL 32224 USA
Univ Cincinnati, Coll Med, Dept Neurol & Rehabil Med, Cincinnati, OH USA
Rosand, J:
Massachusetts Gen Hosp, Ctr Genom Med, Boston, MA 02114 USA
Broad Inst, Program Med & Populat Genet, Cambridge, MA USA
Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA
Anderson, CD:
Massachusetts Gen Hosp, Ctr Genom Med, Boston, MA 02114 USA
Broad Inst, Program Med & Populat Genet, Cambridge, MA USA
Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA
Bronze, Green Published
|