Cerebral small vessel disease genomics and its implications across the lifespan

著者: Muralidharan Sargurupremraj, Hideaki Suzuki, Xueqiu Jian, Chloé Sarnowski, Tavia E. Evans, Joshua C. Bis, Gudny Eiriksdottir, Saori Sakaue, Natalie Terzikhan, Mohamad Habes, Wei Zhao, Nicola J. Armstrong, Edith Hofer, Lisa R. Yanek, Saskia P. Hagenaars, Rajan B. Kumar, Erik B. van den Akker, Rebekah McWhirter, Stella Trompet, Aniket Mishra, Yasaman Saba, Claudia L. Satizábal, Grégory Beaudet, Laurent Petit, Ami Tsuchida, Laure Zago, Sabrina Schilling, Sigurður Sigurðsson, Rebecca F. Gottesman, Cora E. Lewis, Neelum T. Aggarwal, Oscar L. López, Jennifer A. Smith, Maria C. Valdés Hernández, Jeroen van der Grond, Margaret J. Wright, Maria J. Knol, Marcus Dörr, Russell Thomson, Constance Bordes, Quentin Le Grand, Marie‐Gabrielle Duperron, Albert V. Smith, David S. Knopman, Pamela J. Schreiner, Denis A. Evans, Jerome I. Rotter, Alexa Beiser, Susana Muñoz Maniega, Marian Beekman, Julian N. Trollor, David J. Stott, Meike W. Vernooij, Katharina Wittfeld, Wiro J. Niessen, Aïcha Soumaré, Eric Boerwinkle, Stephen Sidney, Stephen T. Turner, Gail Davies, Anbupalam Thalamuthu, Uwe Völker, Mark A. van Buchem, R. Nick Bryan, Josée Dupuis, Mark E. Bastin, David Ames, Alexander Teumer, Philippe Amouyel, John B. Kwok, Robin Bülow, Ian J. Deary, Peter R. Schofield, Henry Brodaty, Jiyang Jiang, Yasuharu Tabara, Kazuya Setoh, Susumu Miyamoto, Kazumichi Yoshida, Manabu Nagata, Yoichiro Kamatani, Fumihiko Matsuda, Bruce M. Psaty, David A. Bennett, Philip L. De Jager, Thomas H. Mosley, Perminder S. Sachdev, Reinhold Schmidt, Helen R. Warren, Εvangelos Εvangelou, David‐Alexandre Trégouët, Philippe Amouyel, Mariza de Andrade, Saonli Basu, Claudine Berr, Jennifer A. Brody, Daniel I. Chasman, Jean‐François Dartigues, Aaron R. Folsom, Marine Germain, Hugoline G. de Haan, John A. Heit, Jeanine Houwing-Duitermaat, Christopher Kabrhel, Peter Kraft, Grégoire Le Gal, Sara Lindström, Ramin Monajemi, Pierre‐Emmanuel Morange, Bruce M. Psaty, P.H. Reitsma, Paul M. Ridker, Lynda Rose, Frits R. Rosendaal, Noémie Saut, P. Eline Slagboom, David M. Smadja, Nicholas L. Smith, Pierre Suchon, Weihong Tang, Kent D. Taylor, David‐Alexandre Trégouët, Christophe Tzourio, Marieke C. Visser, Astrid van Hylckama Vlieg, Lu-Chen Weng, Kerri L. Wiggins, Padhraig Gormley, Verneri Anttila, Bendik S. Winsvold, Priit Palta, Tonu Esko, Tune H. Pers, Kai-How Farh, Ester Cuenca-León, Mikko Muona, Nicholas A. Furlotte, Tobias Kurth, Andrés Ingason, George McMahon, Lannie Ligthart, Gisela M. Terwindt, Mikko Kallela, Tobias Freilinger, Caroline Ran, Scott G. Gordon, Anine H Stam, Stacy Steinberg, Guntram Borck, Markku Koiranen, Lydia Quaye, Hieab H.H. Adams, Terho Lehtimäki, Antti‐Pekka Sarin, Juho Wedenoja, David A. Hinds, Julie E. Buring, Markus Schürks, Paul M. Ridker, Maria Gudlaug Hrafnsdottir, Hreinn Stefánsson, Susan M. Ring, Jouke‐Jan Hottenga, Brenda W. J. H. Penninx, Markus Färkkilä, Ville Artto, Mari Kaunisto, Salli Vepsäläinen, Rainer Malik, Andrew C. Heath, Pamela A. F. Madden, Nicholas G. Martin, Grant W. Montgomery, Mitja Kurki, Mart Kals, Reedik Mägi, Kalle Pärn, Eija Hämäläinen, Hailiang Huang, Andrea Byrnes, Lude Franke, Jie Huang, Evie Stergiakouli, Phil H. Lee, Cynthia Sandor, Caleb Webber, M. Zameel Cader, Bertram Müller‐Myhsok, Stefan Schreiber, Thomas Meitinger, Johan G. Eriksson, Veikko Salomaa, Kauko Heikkilä, Elizabeth Loehrer, Andre G. Uitterlinden, Albert Hofman, Cornelia M. van Duijn, Lynn Cherkas, Linda M. Pedersen, Audun Stubhaug, Christopher Sivert Nielsen, Minna Männikkö, Evelin Mihailov, Lili Milani, Hartmut Göbel, Ann-Louise Esserlind, Anne Francke Christensen, Thomas Folkmann Hansen, Thomas Werge, Jaakko Kaprio, Arpo Aromaa, Olli T. Raitakari, M. Arfan Ikram, Tim D. Spector, Marjo-Riitta Järvelin, Andres Metspalu, Christian Kubisch, David P. Strachan, Michel D. Ferrari, Andrea Carmine Belin, Martin Dichgans, Maija Wessman, Arn M. J. M. van den Maagdenberg, John‐Anker Zwart, Dorret I. Boomsma, George Davey Smith, Kari Stefansson, Nicholas Eriksson, Mark J. Daly, Benjamin M. Neale, Jes Olesen, Daniel I. Chasman, Dale R. Nyholt, Aarno Palotie, M. Arfan Ikram, Wei Wen, Charles DeCarli, Velandai Srikanth, J. Wouter Jukema, P. Eline Slagboom, Sharon L. R. Kardia, Yukinori Okada, Bernard Mazoyer, Joanna M. Wardlaw, Paul Nyquist, Karen A. Mather, Hans J. Grabe, Helena Schmidt, Cornelia M. van Duijn, Vilmundur Guðnason, W.T. Longstreth, Lenore J. Launer, Mark Lathrop, Sudha Seshadri, Christophe Tzourio, Hieab H.H. Adams, Paul M. Matthews, Myriam Fornage, Stéphanie Debette - Nature Communications 2020 被引用: 208

White matter hyperintensities (WMH) are the most common brain-imaging feature of cerebral small vessel disease (SVD), hypertension being the main known risk factor. Here, we identify 27 genome-wide loci for WMH-volume in a cohort of 50,970 older individuals, accounting for modification/confounding by hypertension. Aggregated WMH risk variants were associated with altered white matter integrity (p = 2.5×10-7) in brain images from 1,738 young healthy adults, providing insight into the lifetime impact of SVD genetic risk. Mendelian randomization suggested causal association of increasing WMH-volume with stroke, Alzheimer-type dementia, and of increasing blood pressure (BP) with larger WMH-volume, notably also in persons without clinical hypertension. Transcriptome-wide colocalization analyses showed association of WMH-volume with expression of 39 genes, of which four encode known drug targets. Finally, we provide insight into BP-independent biological pathways underlying SVD and suggest potential for genetic stratification of high-risk individuals and for genetically-informed prioritization of drug targets for prevention trials.