Nature medicine · 2023

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

СтатьяПоддержка NIH: внешняя программаПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод пока не подготовлен

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Duperron Marie-Gabrielle, Knol Maria J, Le Grand Quentin, Evans Tavia E, Mishra Aniket, Tsuchida Ami, Roshchupkin Gennady, Konuma Takahiro, Trégouët David-Alexandre, Romero Jose Rafael, Frenzel Stefan, Luciano Michelle, Hofer Edith, Bourgey Mathieu, Dueker Nicole D, Delgado Pilar, Hilal Saima, Tankard Rick M, Dubost Florian, Shin Jean, Saba Yasaman, Armstrong Nicola J, Bordes Constance, Bastin Mark E, Beiser Alexa, Brodaty Henry, Bülow Robin, Carrera Caty, Chen Christopher, Cheng Ching-Yu, Deary Ian J, Gampawar Piyush G, Himali Jayandra J, Jiang Jiyang, Kawaguchi Takahisa, Li Shuo, Macalli Melissa, Marquis Pascale, Morris Zoe, Muñoz Maniega Susana, Miyamoto Susumu, Okawa Masakazu, Paradise Matthew, Parva Pedram, Rundek Tatjana, Sargurupremraj Muralidharan, Schilling Sabrina, Setoh Kazuya, Soukarieh Omar, Tabara Yasuharu, Teumer Alexander, Thalamuthu Anbupalam, Trollor Julian N, Valdés Hernández Maria C, Vernooij Meike W, Völker Uwe, Wittfeld Katharina, Wong Tien Yin, Wright Margaret J, Zhang Junyi, Zhao Wanting, Zhu Yi-Cheng, Schmidt Helena, Sachdev Perminder S, Wen Wei, Yoshida Kazumichi, Joutel Anne, Satizabal Claudia L, Sacco Ralph L, Bourque Guillaume, CHARGE consortium, Lathrop Mark, Paus Tomas, Fernandez-Cadenas Israel, Yang Qiong, Mazoyer Bernard, Boutinaud Philippe, Okada Yukinori, Grabe Hans J, Mather Karen A, Schmidt Reinhold, Joliot Marc, Ikram M Arfan, Matsuda Fumihiko, Tzourio Christophe, Wardlaw Joanna M, Seshadri Sudha, Adams Hieab H H, Debette Stéphanie

Аннотация

Perivascular space (PVS) burden is an emerging, poorly understood, magnetic resonance imaging marker of cerebral small vessel disease, a leading cause of stroke and dementia. Genome-wide association studies in up to 40,095 participants (18 population-based cohorts, 66.3 ± 8.6 yr, 96.9% European ancestry) revealed 24 genome-wide significant PVS risk loci, mainly in the white matter. These were associated with white matter PVS already in young adults (N = 1,748; 22.1 ± 2.3 yr) and were enriched in early-onset leukodystrophy genes and genes expressed in fetal brain endothelial cells, suggesting early-life mechanisms. In total, 53% of white matter PVS risk loci showed nominally significant associations (27% after multiple-testing correction) in a Japanese population-based cohort (N = 2,862; 68.3 ± 5.3 yr). Mendelian randomization supported causal associations of high blood pressure with basal ganglia and hippocampal PVS, and of basal ganglia PVS and hippocampal PVS with stroke, accounting for blood pressure. Our findings provide insight into the biology of PVS and cerebral small vessel disease, pointing to pathways involving extracellular matrix, membrane transport and developmental processes, and the potential for genetically informed prioritization of drug targets.

Предметные рубрики MeSH

Humans Endothelial Cells Genome-Wide Association Study Cerebral Small Vessel Diseases Stroke Magnetic Resonance Imaging Genomics

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

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Аннотация

Предметные рубрики MeSH