Genomics of perivascular space burden unravels early mechanisms of cerebral small vessel disease

• DOI: 10.1002/alz.064953
• Publication Date: 2022-12-20T15:49:47Z
• Authors: Marie‐Gabrielle D...; Maria J. Knol; Quentin Le Grand; Tavia E Evans; Aniket Mishra; Gennady V. Roshch...; Takahiro Konuma; David Alexandre T...; Jose Rafael Romero; Stefan Frenzel; Michelle Luciano; Edith Hofer; Mathieu Bourgey; Nicole D Dueker; Pilar Delgado; Saima Hilal; Rick M. Tankard; Florian Dubost; Jean Shin; Yasaman Saba; Christopher Chen; Tatjana Rundek; Alexander Teumer; Ami Tsuchida; Helena Schmidt; Perminder S. Sachdev; Wei Wen; Anne Joutel; Claudia L Satizabal; Ralph Sacco; Guillaume Bourque; Mark Lathrop; Tomas Paus; Israel Fernandez‐...; Bernard Mazoyer; Yukinori Okada; Hans J. Grabe; Karen A Mather; Reinhold Schmidt; M. Arfan Ikram; Christophe Tzourio; Joanna M Wardlaw; Sudha Seshadri; Hieab H.H. Adams; Stéphanie Debette
• Keywords: Mendelian Randomization; Genome-wide Association Study; Genetic Association

Abstract Background Perivascular space (PVS) burden is an emerging MRI‐marker of cerebral small vessel disease (cSVD), a leading cause stroke and dementia. Underlying mechanisms PVS are unknown. thought to be related the glymphatic system, involved in brain clearance molecules such as amyloid beta. We aimed decipher genetic underpinnings burden. Method conducted genome‐wide whole‐exome association studies N = 39,823 participants for white matter (WM) PVS, 40,000 basal ganglia (BG) 40,095 hippocampal (HIP) (21 population‐based cohorts, 66.3±8.6 years). As were rated with different scales across we tested variants top quartile distribution each cohort followed by sample‐size weighted meta‐analysis. searched shared variation vascular neurological phenotypes using linkage disequilibrium‐score regression, explored causality associations putative risk factors Mendelian randomization extensive functional exploration identified loci multiple bioinformatics approaches, including transcriptome‐wide studies. Result 24 significant loci. These showed WM already at age 20 1,748 young healthy adults, suggesting important role early‐life factors. enriched genes causing early‐onset leukodystrophies expressed fetal endothelial cells. analyses supported causal high blood pressure BG HIP stroke. Transcriptome‐wide colocalization suggest implication 11 genes, that could prioritized experimental follow‐up. Two‐thirds point novel pathways, involving extracellular matrix, membrane transport, developmental processes, enrichment targets existing drugs cognitive, infectious disorders. Conclusion In this first gene‐mapping study one earliest MRI‐markers cSVD, describe Our findings provide completely insight into biology adult lifespan its contribution cSVD pathophysiology, potential genetically informed prioritization drug prevention trials major dementia worldwide.