Title :

Gene-mapping study of extremes of cerebral small vessel disease reveals TRIM47 as a strong candidate.

Author(s) :

Mishra, Aniket [Auteur]
Bordeaux population health [BPH]
Duplaà, Cécile [Auteur]
Biologie des maladies cardiovasculaires = Biology of Cardiovascular Diseases
Vojinovic, Dina [Auteur]
Suzuki, Hideaki [Auteur]
Sargurupremraj, Muralidharan [Auteur]
Bordeaux population health [BPH]
Zilhão, Nuno R [Auteur]
Li, Shuo [Auteur]
Bartz, Traci M [Auteur]
Jian, Xueqiu [Auteur]
Zhao, Wei [Auteur]
Hofer, Edith [Auteur]
Wittfeld, Katharina [Auteur]
Harris, Sarah E [Auteur]
van Der Auwera-Palitschka, Sandra [Auteur]
Luciano, Michelle [Auteur]
Bis, Joshua C [Auteur]
Adams, Hieab H H [Auteur]
Satizabal, Claudia L [Auteur]
Gottesman, Rebecca F [Auteur]
Gampawar, Piyush G [Auteur]
Bülow, Robin [Auteur]
Weiss, Stefan [Auteur]
Yu, Miao [Auteur]
Bastin, Mark E [Auteur]
Lopez, Oscar L [Auteur]
Vernooij, Meike W [Auteur]
Beiser, Alexa S [Auteur]
Völker, Uwe [Auteur]
Kacprowski, Tim [Auteur]
Soumare, Aicha [Auteur]
Bordeaux population health [BPH]
Smith, Jennifer A [Auteur]
Knopman, David S [Auteur]
Morris, Zoe [Auteur]
Zhu, Yicheng [Auteur]
Rotter, Jerome I [Auteur]
Dufouil, Carole [Auteur]
Bordeaux population health [BPH]
Valdés Hernández, Maria [Auteur]
Muñoz Maniega, Susana [Auteur]
Lathrop, Mark [Auteur]
Boerwinkle, Erik [Auteur]
Schmidt, Reinhold [Auteur]
Ihara, Masafumi [Auteur]
Mazoyer, Bernard [Auteur]
Yang, Qiong [Auteur]
Joutel, Anne [Auteur]
Institut de psychiatrie et neurosciences de Paris [IPNP - U1266 Inserm]
Tournier-Lasserve, Elizabeth [Auteur]
Maladies neurodéveloppementales et neurovasculaires [NeuroDiderot (UMR_S_1141 / U1141)]
Launer, Lenore J [Auteur]
Deary, Ian J [Auteur]
Mosley, Thomas H [Auteur]
Amouyel, Philippe [Auteur]
Facteurs de Risque et Déterminants Moléculaires des Maladies liées au Vieillissement - U 1167 [RID-AGE]
Decarli, Charles S [Auteur]
Psaty, Bruce M [Auteur]
Tzourio, Christophe [Auteur]
Kardia, Sharon L R [Auteur]
Grabe, Hans J [Auteur]
Teumer, Alexander [Auteur]
van Duijn, Cornelia M [Auteur]
Schmidt, Helena [Auteur]
Wardlaw, Joanna M [Auteur]
Ikram, M Arfan [Auteur]
Fornage, Myriam [Auteur]
Gudnason, Vilmundur [Auteur]
Seshadri, Sudha [Auteur]
Matthews, Paul M [Auteur]
Longstreth, William T [Auteur]
Couffinhal, Thierry [Auteur]
Biologie des maladies cardiovasculaires = Biology of Cardiovascular Diseases
Debette, Stephanie [Auteur]
Bordeaux population health [BPH]

Journal title :

Brain - A Journal of Neurology

Publisher :

Oxford University Press

Publication date :

2022-05-02

ISSN :

0006-8950

Keyword(s) :

ARTICLE RECHERCHE

English keyword(s) :

GWAS
TRIM47
cerebral small vessel disease
endothelial cells
whole-exome association study

HAL domain(s) :

Sciences du Vivant [q-bio]/Médecine humaine et pathologie

English abstract : [en]

Cerebral small vessel disease is a leading cause of stroke and a major contributor to cognitive decline and dementia, but our understanding of specific genes underlying the cause of sporadic cerebral small vessel disease ...
Show more >Cerebral small vessel disease is a leading cause of stroke and a major contributor to cognitive decline and dementia, but our understanding of specific genes underlying the cause of sporadic cerebral small vessel disease is limited. We report a genome-wide association study and a whole-exome association study on a composite extreme phenotype of cerebral small vessel disease derived from its most common MRI features: white matter hyperintensities and lacunes. Seventeen population-based cohorts of older persons with MRI measurements and genome-wide genotyping (n = 41 326), whole-exome sequencing (n = 15 965), or exome chip (n = 5249) data contributed 13 776 and 7079 extreme small vessel disease samples for the genome-wide association study and whole-exome association study, respectively. The genome-wide association study identified significant association of common variants in 11 loci with extreme small vessel disease, of which the chr12q24.11 locus was not previously reported to be associated with any MRI marker of cerebral small vessel disease. The whole-exome association study identified significant associations of extreme small vessel disease with common variants in the 5' UTR region of EFEMP1 (chr2p16.1) and one probably damaging common missense variant in TRIM47 (chr17q25.1). Mendelian randomization supports the causal association of extensive small vessel disease severity with increased risk of stroke and Alzheimer's disease. Combined evidence from summary-based Mendelian randomization studies and profiling of human loss-of-function allele carriers showed an inverse relation between TRIM47 expression in the brain and blood vessels and extensive small vessel disease severity. We observed significant enrichment of Trim47 in isolated brain vessel preparations compared to total brain fraction in mice, in line with the literature showing Trim47 enrichment in brain endothelial cells at single cell level. Functional evaluation of TRIM47 by small interfering RNAs-mediated knockdown in human brain endothelial cells showed increased endothelial permeability, an important hallmark of cerebral small vessel disease pathology. Overall, our comprehensive gene-mapping study and preliminary functional evaluation suggests a putative role of TRIM47 in the pathophysiology of cerebral small vessel disease, making it an important candidate for extensive in vivo explorations and future translational work.Show less >

Language :

Anglais

Peer reviewed article :

Oui

Audience :

Internationale

Popular science :

Non

ANR Project :

Stopping cognitive decline and dementia by fighting covert cerebral small vessel disease

Collections :

• Facteurs de risque et déterminants moléculaires des maladies liées au vieillissement (RID-AGE) - U1167

Source :

Harvested from HAL