Association of variants in HTRA1 and NOTCH3 ...
Document type :
Compte-rendu et recension critique d'ouvrage
DOI :
PMID :
Title :
Association of variants in HTRA1 and NOTCH3 with MRI-defined extremes of cerebral small vessel disease in older subjects
Author(s) :
Mishra, Aniket [Auteur correspondant]
Bordeaux population health [BPH]
Chauhan, Ganesh [Auteur]
Bordeaux population health [BPH]
Indian Institute of Science [Bangalore] [IISc Bangalore]
Violleau, Marie-Helene [Auteur]
Bordeaux population health [BPH]
Vojinovic, Dina [Auteur]
Erasmus University Medical Center [Rotterdam] [Erasmus MC]
Jian, Xueqiu [Auteur]
The University of Texas Health Science Center at Houston [UTHealth]
Bis, Joshua C [Auteur]
University of Washington [Seattle]
Li, Shuo [Auteur]
School of Public Health [Boston]
Saba, Yasaman [Auteur]
Medical University Graz
Grenier-Boley, Benjamin [Auteur]
Facteurs de Risque et Déterminants Moléculaires des Maladies liées au Vieillissement - U 1167 [RID-AGE]
Yang, Qiong [Auteur]
School of Public Health [Boston]
Boston University School of Medicine [BUSM]
Bartz, Traci M [Auteur]
University of Washington [Seattle]
Hofer, Edith [Auteur]
Medical University Graz
Soumaré, Aïcha [Auteur]
Bordeaux population health [BPH]
Peng, Fen [Auteur]
The University of Texas Health Science Center at Houston [UTHealth]
Duperron, Marie-Gabrielle [Auteur]
Bordeaux population health [BPH]
Foglio, Mario [Auteur]
McGill University = Université McGill [Montréal, Canada]
Mosley, Thomas H [Auteur]
University of Mississippi Medical Center [UMMC]
Schmidt, Reinhold [Auteur]
Medical University Graz
Psaty, Bruce M [Auteur]
University of Washington [Seattle]
Kaiser Permanente Washington Health Research Institute [Seattle] [KPWHRI]
Launer, Lenore J [Auteur]
National Institutes of Health [Bethesda, MD, USA] [NIH]
Boerwinkle, Eric [Auteur]
The University of Texas Health Science Center at Houston [UTHealth]
Zhu, Yicheng [Auteur]
Peking Union Medical College Hospital [Beijing] [PUMCH]
Mazoyer, Bernard [Auteur]
Institut des Maladies Neurodégénératives [Bordeaux] [IMN]
Lathrop, Mark [Auteur]
McGill University = Université McGill [Montréal, Canada]
Bellenguez, Celine [Auteur]
Facteurs de Risque et Déterminants Moléculaires des Maladies liées au Vieillissement - U 1167 [RID-AGE]
van Duijn, Cornelia M [Auteur]
Erasmus University Medical Center [Rotterdam] [Erasmus MC]
University of Oxford
Ikram, M Arfan [Auteur]
Erasmus University Medical Center [Rotterdam] [Erasmus MC]
Schmidt, Helena [Auteur]
Medical University Graz
Longstreth, W T [Auteur]
University of Washington [Seattle]
Fornage, Myriam [Auteur]
The University of Texas Health Science Center at Houston [UTHealth]
Seshadri, Sudha [Auteur]
The University of Texas at San Antonio [UTSA]
Boston University School of Medicine [BUSM]
Joutel, Anne [Auteur]
Institut de psychiatrie et neurosciences de Paris [IPNP - U1266 Inserm]
Tzourio, Christophe [Auteur]
Bordeaux population health [BPH]
CHU Bordeaux
Debette, Stephanie [Auteur correspondant]
Bordeaux population health [BPH]
Boston University School of Medicine [BUSM]
CHU Bordeaux
Bordeaux population health [BPH]
Chauhan, Ganesh [Auteur]
Bordeaux population health [BPH]
Indian Institute of Science [Bangalore] [IISc Bangalore]
Violleau, Marie-Helene [Auteur]
Bordeaux population health [BPH]
Vojinovic, Dina [Auteur]
Erasmus University Medical Center [Rotterdam] [Erasmus MC]
Jian, Xueqiu [Auteur]
The University of Texas Health Science Center at Houston [UTHealth]
Bis, Joshua C [Auteur]
University of Washington [Seattle]
Li, Shuo [Auteur]
School of Public Health [Boston]
Saba, Yasaman [Auteur]
Medical University Graz
Grenier-Boley, Benjamin [Auteur]
Facteurs de Risque et Déterminants Moléculaires des Maladies liées au Vieillissement - U 1167 [RID-AGE]
Yang, Qiong [Auteur]
School of Public Health [Boston]
Boston University School of Medicine [BUSM]
Bartz, Traci M [Auteur]
University of Washington [Seattle]
Hofer, Edith [Auteur]
Medical University Graz
Soumaré, Aïcha [Auteur]
Bordeaux population health [BPH]
Peng, Fen [Auteur]
The University of Texas Health Science Center at Houston [UTHealth]
Duperron, Marie-Gabrielle [Auteur]
Bordeaux population health [BPH]
Foglio, Mario [Auteur]
McGill University = Université McGill [Montréal, Canada]
Mosley, Thomas H [Auteur]
University of Mississippi Medical Center [UMMC]
Schmidt, Reinhold [Auteur]
Medical University Graz
Psaty, Bruce M [Auteur]
University of Washington [Seattle]
Kaiser Permanente Washington Health Research Institute [Seattle] [KPWHRI]
Launer, Lenore J [Auteur]
National Institutes of Health [Bethesda, MD, USA] [NIH]
Boerwinkle, Eric [Auteur]
The University of Texas Health Science Center at Houston [UTHealth]
Zhu, Yicheng [Auteur]
Peking Union Medical College Hospital [Beijing] [PUMCH]
Mazoyer, Bernard [Auteur]
Institut des Maladies Neurodégénératives [Bordeaux] [IMN]
Lathrop, Mark [Auteur]
McGill University = Université McGill [Montréal, Canada]
Bellenguez, Celine [Auteur]
![refId](/themes/Mirage2//images/idref.png)
Facteurs de Risque et Déterminants Moléculaires des Maladies liées au Vieillissement - U 1167 [RID-AGE]
van Duijn, Cornelia M [Auteur]
Erasmus University Medical Center [Rotterdam] [Erasmus MC]
University of Oxford
Ikram, M Arfan [Auteur]
Erasmus University Medical Center [Rotterdam] [Erasmus MC]
Schmidt, Helena [Auteur]
Medical University Graz
Longstreth, W T [Auteur]
University of Washington [Seattle]
Fornage, Myriam [Auteur]
The University of Texas Health Science Center at Houston [UTHealth]
Seshadri, Sudha [Auteur]
The University of Texas at San Antonio [UTSA]
Boston University School of Medicine [BUSM]
Joutel, Anne [Auteur]
Institut de psychiatrie et neurosciences de Paris [IPNP - U1266 Inserm]
Tzourio, Christophe [Auteur]
Bordeaux population health [BPH]
CHU Bordeaux
Debette, Stephanie [Auteur correspondant]
Bordeaux population health [BPH]
Boston University School of Medicine [BUSM]
CHU Bordeaux
Journal title :
Brain - A Journal of Neurology
Pages :
1009-1023
Publisher :
Oxford University Press
Publication date :
2019-03-11
ISSN :
0006-8950
English keyword(s) :
white matter hyperintensity
lacunes of presumed vascular origin
extreme phenotype
exome sequencing study
cerebral small vessel disease
lacunes of presumed vascular origin
extreme phenotype
exome sequencing study
cerebral small vessel disease
HAL domain(s) :
Sciences du Vivant [q-bio]/Génétique/Génétique humaine
Sciences du Vivant [q-bio]/Génétique/Génétique des populations [q-bio.PE]
Sciences du Vivant [q-bio]/Neurosciences [q-bio.NC]/Neurobiologie
Sciences du Vivant [q-bio]/Médecine humaine et pathologie/Gériatrie et gérontologie
Sciences du Vivant [q-bio]/Génétique/Génétique des populations [q-bio.PE]
Sciences du Vivant [q-bio]/Neurosciences [q-bio.NC]/Neurobiologie
Sciences du Vivant [q-bio]/Médecine humaine et pathologie/Gériatrie et gérontologie
English abstract : [en]
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 ...
Show more >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.Show less >
Show more >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.Show less >
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Anglais
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