| Title: |
Cerebral small vessel disease genomics and its implications across the lifespan |
| Authors: |
Sargurupremraj, Muralidharan; Suzuki, Hideaki; Jian, Xueqiu; Sarnowski, Chloé; Evans, Tavia E.; Bis, Joshua C.; Eiriksdottir, Gudny; Sakaue, Saori; Terzikhan, Natalie; Habes, Mohamad; Zhao, Wei; Armstrong, Nicola J.; Hofer, Edith; Yanek, Lisa R.; Hagenaars, Saskia P.; Kumar, Rajan B.; van den Akker, Erik B.; McWhirter, Rebekah E.; Trompet, Stella; Mishra, Aniket; Saba, Yasaman; Satizabal, Claudia L.; Beaudet, Gregory; Petit, Laurent; Tsuchida, Ami; Zago, Laure; Schilling, Sabrina; Sigurdsson, Sigurdur; Gottesman, Rebecca F.; Lewis, Cora E.; Aggarwal, Neelum T.; Lopez, Oscar L.; Smith, Jennifer A.; Valdés Hernández, Maria C.; van der Grond, Jeroen; Wright, Margaret J.; Knol, Maria J.; Dörr, Marcus; Thomson, Russell J.; Bordes, Constance; Le Grand, Quentin; Duperron, Marie-Gabrielle; Smith, Albert V.; Knopman, David S.; Schreiner, Pamela J.; Evans, Denis A.; Rotter, Jerome I.; Beiser, Alexa S.; Maniega, Susana Muñoz; Beekman, Marian; Trollor, Julian; Stott, David J.; Vernooij, Meike W.; Wittfeld, Katharina; Niessen, Wiro J.; Soumaré, Aicha; Boerwinkle, Eric; Sidney, Stephen; Turner, Stephen T.; Davies, Gail; Thalamuthu, Anbupalam; Völker, Uwe; van Buchem, Mark A.; Bryan, R. Nick; Dupuis, Josée; Bastin, Mark E.; Ames, David; Teumer, Alexander; Amouyel, Philippe; Kwok, John B.; Bülow, Robin; Deary, Ian J.; Schofield, Peter R.; Brodaty, Henry; Jiang, Jiyang; Tabara, Yasuharu; Setoh, Kazuya; Miyamoto, Susumu; Yoshida, Kazumichi; Nagata, Manabu; Kamatani, Yoichiro; Matsuda, Fumihiko; Psaty, Bruce M.; Bennett, David A.; De Jager, Philip L.; Mosley, Thomas H.; Sachdev, Perminder S.; Schmidt, Reinhold; Warren, Helen R.; Evangelou, Evangelos; Trégouët, David-Alexandre; Ikram, Mohammad A.; Wen, Wei; DeCarli, Charles; Srikanth, Velandai K.; Jukema, J. Wouter; Slagboom, Eline P.; Kardia, Sharon L. R.; Okada, Yukinori; Mazoyer, Bernard; Wardlaw, Joanna M.; Nyquist, Paul A.; Mather, Karen A.; Grabe, Hans J.; Schmidt, Helena; Van Duijn, Cornelia M.; Gudnason, Vilmundur; Longstreth, William T.; Launer, Lenore J.; Lathrop, Mark; Seshadri, Sudha; Tzourio, Christophe; Adams, Hieab H.; Matthews, Paul M.; Fornage, Myriam; Debette, Stéphanie; de Andrade, Mariza; Basu, Saonli; Berr, Claudine; Brody, Jennifer A.; Chasman, Daniel I.; Dartigues, Jean-Francois; Folsom, Aaron R.; Germain, Marine; de Haan, Hugoline; Heit, John; Houwing-Duitermaat, Jeanine; Kabrhel, Christopher; Kraft, Peter; Legal, Grégoire; Lindström, Sara; Monajemi, Ramin; Morange, Pierre-Emmanuel; Reitsma, Pieter H.; Ridker, Paul M.; Rose, Lynda M.; Rosendaal, Frits R.; Saut, Noémie; Slagboom, Eline; Smadja, David; Smith, Nicholas L.; Suchon, Pierre; Tang, Weihong; Taylor, Kent D.; de Visser, Marieke C. H.; van Hylckama Vlieg, Astrid; Weng, Lu-Chen; Wiggins, Kerri L.; Gormley, Padhraig; Anttila, Verneri; Winsvold, Bendik S.; Palta, Priit; Esko, Tonu; Pers, Tune H.; Farh, Kai-How; Cuenca-Leon, Ester; Muona, Mikko; Furlotte, Nicholas A.; Kurth, Tobias; Ingason, Andres; McMahon, George; Ligthart, Lannie; Terwindt, Gisela M.; Kallela, Mikko; Freilinger, Tobias M.; Ran, Caroline; Gordon, Scott G.; Stam, Anine H.; Steinberg, Stacy; Borck, Guntram; Koiranen, Markku; Quaye, Lydia; Adams, Hieab H. H.; Lehtimäki, Terho; Sarin, Antti-Pekka; Wedenoja, Juho; Hinds, David A.; Buring, Julie E.; Schürks, Markus; Gudlaug Hrafnsdottir, Maria; Stefansson, Hreinn; Ring, Susan M.; Hottenga, Jouke-Jan; Penninx, Brenda W. J. H.; Färkkilä, Markus; Artto, Ville; Kaunisto, Mari; Vepsäläinen, Salli; Malik, Rainer; Heath, Andrew C.; Madden, Pamela A. F.; Martin, Nicholas G.; Montgomery, Grant W.; Kurki, Mitja; Kals, Mart; Mägi, Reedik; Pärn, Kalle; Hämäläinen, Eija; Huang, Hailiang; Byrnes, Andrea E.; Franke, Lude; Huang, Jie; Stergiakouli, Evie; Lee, Phil H.; Sandor, Cynthia; Webber, Caleb; Cader, Zameel; Muller-Myhsok, Bertram; Schreiber, Stefan; Meitinger, Thomas; Eriksson, Johan G.; Salomaa, Veikko; Heikkilä, Kauko; Loehrer, Elizabeth; Uitterlinden, Andre G.; Hofman, Albert; van Duijn, Cornelia M.; Cherkas, Lynn; Pedersen, Linda M.; Stubhaug, Audun; Nielsen, Christopher S.; Männikkö, Minna; Mihailov, Evelin; Milani, Lili; Göbel, Hartmut; Esserlind, Ann-Louise; Francke Christensen, Anne; Folkmann Hansen, Thomas; Werge, Thomas; Kaprio, Jaakko; Aromaa, Arpo J.; Raitakari, Olli; Ikram, M. Arfan; Spector, Tim; Järvelin, Marjo-Riitta; Metspalu, Andres; Kubisch, Christian; Strachan, David P.; Ferrari, Michel D.; Belin, Andrea C.; Dichgans, Martin; Wessman, Maija; van den Maagdenberg, Arn M. J. M.; Zwart, John-Anker; Boomsma, Dorret I.; Davey Smith, George; Stefansson, Kari; Eriksson, Nicholas; Daly, Mark J.; Neale, Benjamin M.; Olesen, Jes; Nyholt, Dale R.; Palotie, Aarno |
| Publisher Information: |
Nature Research |
| Publication Year: |
2020 |
| Collection: |
University of Glasgow: Enlighten - Publications |
| Description: |
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. |
| Document Type: |
article in journal/newspaper |
| File Description: |
text |
| Language: |
English |
| Relation: |
https://eprints.gla.ac.uk/230508/1/230508.pdf; Sargurupremraj, M. et al. (2020) Cerebral small vessel disease genomics and its implications across the lifespan. Nature Communications , 11, 6285. (doi:10.1038/s41467-020-19111-2 ) (PMID:33293549) (PMCID:PMC7722866) |
| Availability: |
https://eprints.gla.ac.uk/230508/; https://eprints.gla.ac.uk/230508/1/230508.pdf |
| Rights: |
cc_by_4 |
| Accession Number: |
edsbas.CD440AD8 |
| Database: |
BASE |