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Brain, Published: 20 August 2019, awz233 | https://doi.org/10.1093/brain/awz233 Genome-wide association study of cerebral small vessel disease reveals established and novel loci

Jaeyoon Chung,^1,2 Sandro Marini,^1,2 Joanna Pera,³ Bo Norrving,^4,5Jordi Jimenez-Conde,⁶ Jaume Roquer,⁶ Israel Fernandez-Cadenas,^7,8David L. Tirschwell,⁹ Magdy Selim,¹⁰ Devin L. Brown,¹¹Scott L. Silliman,¹² Bradford B. Worrall,¹³James F. Meschia,¹⁴ Stacie Demel,¹⁵ Steven M. Greenberg,¹⁶ Agnieszka Slowik,³ Arne Lindgren,^4,5 Reinhold Schmidt,¹⁷ Matthew Traylor,¹⁸Muralidharan Sargurupremraj,¹⁹ Steffen Tiedt,^20,21Rainer Malik,^20,21Stéphanie Debette,^19,22Martin Dichgans,^20,21,23Carl D. Langefeld,²⁴ Daniel Woo,¹⁵ Jonathan Rosand^1,2,25and Christopher D. Anderson^1,2,25on behalf of the International Stroke Genetics Consortium

¹ Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA
²Program in Medical and Population Genetics, Broad Institute, Cambridge, MA, USA
³ Department of Neurology, Jagiellonian University Medical College, Krakow, Poland
⁴ Department of Clinical Sciences Lund, Neurology, Lund University, Lund, Sweden
⁵ Department of Neurology and Rehabilitation Medicine, Ska˚ne University Hospital, Lund, Sweden
⁶ Department of Neurology, Neurovascular Research Unit, Institut Hospital del Mar d’Investigacions Mèdiques, Universitat Autonoma de Barcelona, Barcelona, Spain
⁷Neurovascular Research Laboratory and Neurovascular Unit, Institut de Recerca, Hospital Vall d’Hebron, Universitat Autonoma de Barcelona, Barcelona, Spain
⁸Stroke Pharmacogenomics and Genetics, Sant Pau Institute of Research, Hospital de la Santa Creu I Sant Pau, Barcelona, Spain
⁹Stroke Center, Harborview Medical Center, University of Washington, Seattle, WA, USA
¹⁰ Department of Neurology, Stroke Division, Beth Israel Deaconess Medical Center, Boston, MA, USA
¹¹Stroke Program, Department of Neurology, University of Michigan, Ann Arbor, MI, USA
¹² Department of Neurology, University of Florida College of Medicine, Jacksonville, FL, USA
¹³ Department of Neurology and Public Health Sciences, University of Virginia Health System, Charlottesville, VA, USA
¹⁴Department of Neurology, Mayo Clinic, Jacksonville, FL, USA
¹⁵ Department of Neurology and Rehabilitation Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, USA
¹⁶ The J. Philip Kistler Stroke Research Center, Massachusetts General Hospital, Boston, MA, USA
¹⁷Department of Neurology, Medical University of Graz, Graz, Austria
¹⁸ Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK
¹⁹University of Bordeaux, INSERM U1219, Bordeaux Population Health Research Center, Bordeaux, France
²⁰ Institute for Stroke and Dementia Research, University Hospital, LMU Munich, Munich, Germany
²¹ Munich Cluster for Systems Neurology (SyNergy), Munich, Germany
²² Department of Neurology, Memory Clinic, Bordeaux University Hospital, University of Bordeaux, Bordeaux, France
²³ German Center for Neurodegenerative Diseases (DZNE, Munich), Munich, Germany
²⁴Center for Public Health Genomics and Department of Biostatistical Sciences, Wake Forest School of Medicine, Winston-Salem, NC, USA
²⁵ Department of Neurology, Massachusetts General Hospital, Boston, MA, USA

^*Correspondence to: Dr Christopher D. Anderson 185 Cambridge Street, CPZN 6–818 Boston, MA 02114, USA

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.

Keywords: genome-wide association studies, cerebral small vessel disease, multi-trait analysis

논문정보

형식Research article
게재일2019년 08월 (BRIC 등록일 2019-09-10)
연구진국외 연구진
분야 생명과학 > 유전학

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