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Brain. 2019 Apr 1;142(4):1009-1023. doi: 10.1093/brain/awz024.

Association of variants in HTRA1 and NOTCH3 with MRI-defined extremes of cerebral small vessel disease in older subjects.

Author information

1
University of Bordeaux, Inserm, Bordeaux Population Health Research Center, team VINTAGE, UMR 1219, F-33000 Bordeaux, France.
2
Centre for Brain Research, Indian Institute of Science, Bangalore, India.
3
Department of Epidemiology, Erasmus MC, University Medical Center, Rotterdam, The Netherlands.
4
The University of Texas Health Science Center at Houston, Houston, TX, USA.
5
Department of Biostatistics, University of Washington, Seattle, WA, USA.
6
Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA.
7
Gottfried Schatz Research Center, Department of Molecular Biology and Biochemistry, Medical University of Graz, Graz, Austria.
8
Inserm, U1167, RID-AGE - Risk factors and molecular determinants of aging-related diseases, F-59000 Lille, France.
9
 Institut Pasteur de Lille, F-59000 Lille, France.
10
Univ. Lille, U1167 - Excellence Laboratory LabEx DISTALZ, F-59000 Lille, France.
11
Department of Neurology, Boston University School of Medicine, Boston, MA, USA.
12
Cardiovascular Health Research Unit, Departments of Biostatistics and Medicine, University of Washington, Seattle, WA, USA.
13
Clinical Division of Neurogeriatrics, Department of Neurology, Medical University of Graz, Austria.
14
Institute for Medical Informatics, Statistics and Documentation, Medical University of Graz, Austria.
15
University of McGill Genome Center, Montreal, Canada.
16
Division of Geriatrics, School of Medicine, University of Mississippi Medical Center, Jackson, MS, USA.
17
Memory Impairment and Neurodegenerative Dementia Center, University of Mississippi Medical Center, Jackson, MS, USA.
18
Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA.
19
Department of Epidemiology, University of Washington, Seattle, WA, USA.
20
Department of Health Services, University of Washington, Seattle, WA, USA.
21
Kaiser Permanente Washington Health Research Institute, Seattle, WA, USA.
22
Intramural Research Program, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA.
23
Department of Neurology, Peking Union Medical College Hospital, Beijing, China.
24
University of Bordeaux, Institut des Maladies Neurodégénératives, CNRS-CEA UMR 5293, France.
25
Nuffield Department of Population Health, University of Oxford, Oxford, UK.
26
Department of Radiology and Nuclear Medicine, Erasmus MC, University Medical Center, Rotterdam, The Netherlands.
27
Department of Neurology and Department of Epidemiology, University of Washington, Seattle, WA, USA.
28
Glenn Biggs Institute for Alzheimer's and Neurodegenerative Diseases, University of Texas Health Sciences Center, San Antonio, Texas, USA.
29
Institute of Psychiatry and Neurosciences of Paris, Inserm, University Paris Descartes, DHU NeuroVasc, Sorbonne Paris Cité, Paris, France.
30
CHU de Bordeaux, Pole de santé publique, Service d'information médicale, F-33000 Bordeaux, France.
31
CHU de Bordeaux, Department of Neurology, F-33000 Bordeaux, France.

Abstract

We report a composite extreme phenotype design using distribution of white matter hyperintensities and brain infarcts in a population-based cohort of older persons for gene-mapping of cerebral small vessel disease. We demonstrate its application in the 3C-Dijon whole exome sequencing (WES) study (n = 1924, nWESextremes = 512), with both single variant and gene-based association tests. We used other population-based cohort studies participating in the CHARGE consortium for replication, using whole exome sequencing (nWES = 2,868, nWESextremes = 956) and genome-wide genotypes (nGW = 9924, nGWextremes = 3308). We restricted our study to candidate genes known to harbour mutations for Mendelian small vessel disease: NOTCH3, HTRA1, COL4A1, COL4A2 and TREX1. We identified significant associations of a common intronic variant in HTRA1, rs2293871 using single variant association testing (Pdiscovery = 8.21 × 10-5, Preplication = 5.25 × 10-3, Pcombined = 4.72 × 10-5) and of NOTCH3 using gene-based tests (Pdiscovery = 1.61 × 10-2, Preplication = 3.99 × 10-2, Pcombined = 5.31 × 10-3). Follow-up analysis identified significant association of rs2293871 with small vessel ischaemic stroke, and two blood expression quantitative trait loci of HTRA1 in linkage disequilibrium. Additionally, we identified two participants in the 3C-Dijon cohort (0.4%) carrying heterozygote genotypes at known pathogenic variants for familial small vessel disease within NOTCH3 and HTRA1. In conclusion, our proof-of-concept study provides strong evidence that using a novel composite MRI-derived phenotype for extremes of small vessel disease can facilitate the identification of genetic variants underlying small vessel disease, both common variants and those with rare and low frequency. The findings demonstrate shared mechanisms and a continuum between genes underlying Mendelian small vessel disease and those contributing to the common, multifactorial form of the disease.

KEYWORDS:

cerebral small vessel disease; exome sequencing study; extreme phenotype; lacunes of presumed vascular origin; white matter hyperintensity

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