Gene-mapping study of extremes of cerebral small vessel disease reveals TRIM47 as a strong candidate
Authors: Mishra Aniket , Duplaà Cécile , Vojinovic Dina , Suzuki Hideaki , Sargurupremraj Muralidharan , Zilhão Nuno R , Li Shuo , Bartz Traci M , Jian Xueqiu , Zhao Wei , Hofer Edith , Wittfeld Katharina , Harris Sarah E , van der Auwera-Palitschka Sandra , Luciano Michelle , Bis Joshua C , Adams Hieab H H , Satizabal Claudia L , Gottesman Rebecca F , Gampawar Piyush G , Bülow Robin , Weiss Stefan , Yu Miao , Bastin Mark E , Lopez Oscar L , Vernooij Meike W , Beiser Alexa S , Völker Uwe , Kacprowski Tim , Soumare Aicha , Smith Jennifer A , Knopman David S , Morris Zoe , Zhu Yicheng , Rotter Jerome I , Dufouil Carole , Valdés Hernández Maria , Muñoz Maniega Susana , Lathrop Mark , Boerwinkle Erik , Schmidt Reinhold , Ihara Masafumi , Mazoyer Bernard , Yang Qiong , Joutel Anne , Tournier-Lasserve Elizabeth , Launer Lenore J , Deary Ian J , Mosley Thomas H , Amouyel Philippe , DeCarli Charles S , Psaty Bruce M , Tzourio Christophe , Kardia Sharon L R , Grabe Hans J , Teumer Alexander , van Duijn Cornelia M , Schmidt Helena , Wardlaw Joanna M , Ikram M Arfan , Fornage Myriam , Gudnason Vilmundur , Seshadri Sudha , Matthews Paul M , Longstreth William T , Couffinhal Thierry , Debette Stephanie 
Published: December 2021

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.