Cerebral small vessel disease genomics and its implications across the lifespan

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)

Abstract

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.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Stott J, Professor David
• Authors: Sargurupremraj, M., Suzuki, H., Jian, X., Sarnowski, C., Evans, T. E., Bis, J. C., Eiriksdottir, G., Sakaue, S., Terzikhan, N., Habes, M., Zhao, W., Armstrong, N. J., Hofer, E., Yanek, L. R., Hagenaars, S. P., Kumar, R. B., van den Akker, E. B., McWhirter, R. E., Trompet, S., Mishra, A., Saba, Y., Satizabal, C. L., Beaudet, G., Petit, L., Tsuchida, A., Zago, L., Schilling, S., Sigurdsson, S., Gottesman, R. F., Lewis, C. E., Aggarwal, N. T., Lopez, O. L., Smith, J. A., Valdés Hernández, M. C., van der Grond, J., Wright, M. J., Knol, M. J., Dörr, M., Thomson, R. J., Bordes, C., Le Grand, Q., Duperron, M.-G., Smith, A. V., Knopman, D. S., Schreiner, P. J., Evans, D. A., Rotter, J. I., Beiser, A. S., Maniega, S. M., Beekman, M., Trollor, J., Stott, D. J., Vernooij, M. W., Wittfeld, K., Niessen, W. J., Soumaré, A., Boerwinkle, E., Sidney, S., Turner, S. T., Davies, G., Thalamuthu, A., Völker, U., van Buchem, M. A., Bryan, R. N., Dupuis, J., Bastin, M. E., Ames, D., Teumer, A., Amouyel, P., Kwok, J. B., Bülow, R., Deary, I. J., Schofield, P. R., Brodaty, H., Jiang, J., Tabara, Y., Setoh, K., Miyamoto, S., Yoshida, K., Nagata, M., Kamatani, Y., Matsuda, F., Psaty, B. M., Bennett, D. A., De Jager, P. L., Mosley, T. H., Sachdev, P. S., Schmidt, R., Warren, H. R., Evangelou, E., Trégouët, D.-A., Ikram, M. A., Wen, W., DeCarli, C., Srikanth, V. K., Jukema, J. W., Slagboom, E. P., Kardia, S. L. R., Okada, Y., Mazoyer, B., Wardlaw, J. M., Nyquist, P. A., Mather, K. A., Grabe, H. J., Schmidt, H., Van Duijn, C. M., Gudnason, V., Longstreth, W. T., Launer, L. J., Lathrop, M., Seshadri, S., Tzourio, C., Adams, H. H., Matthews, P. M., Fornage, M., Debette, S., Amouyel, P., de Andrade, M., Basu, S., Berr, C., Brody, J. A., Chasman, D. I., Dartigues, J.-F., Folsom, A. R., Germain, M., de Haan, H., Heit, J., Houwing-Duitermaat, J., Kabrhel, C., Kraft, P., Legal, G., Lindström, S., Monajemi, R., Morange, P.-E., Psaty, B. M., Reitsma, P. H., Ridker, P. M., Rose, L. M., Rosendaal, F. R., Saut, N., Slagboom, E., Smadja, D., Smith, N. L., Suchon, P., Tang, W., Taylor, K. D., Trégouët, D.-A., Tzourio, C., de Visser, M. C. H., van Hylckama Vlieg, A., Weng, L.-C., Wiggins, K. L., Gormley, P., Anttila, V., Winsvold, B. S., Palta, P., Esko, T., Pers, T. H., Farh, K.-H., Cuenca-Leon, E., Muona, M., Furlotte, N. A., Kurth, T., Ingason, A., McMahon, G., Ligthart, L., Terwindt, G. M., Kallela, M., Freilinger, T. M., Ran, C., Gordon, S. G., Stam, A. H., Steinberg, S., Borck, G., Koiranen, M., Quaye, L., Adams, H. H. H., Lehtimäki, T., Sarin, A.-P., Wedenoja, J., Hinds, D. A., Buring, J. E., Schürks, M., Ridker, P. M., Gudlaug Hrafnsdottir, M., Stefansson, H., Ring, S. M., Hottenga, J.-J., Penninx, B. W. J. H., Färkkilä, M., Artto, V., Kaunisto, M., Vepsäläinen, S., Malik, R., Heath, A. C., Madden, P. A. F., Martin, N. G., Montgomery, G. W., Kurki, M., Kals, M., Mägi, R., Pärn, K., Hämäläinen, E., Huang, H., Byrnes, A. E., Franke, L., Huang, J., Stergiakouli, E., Lee, P. H., Sandor, C., Webber, C., Cader, Z., Muller-Myhsok, B., Schreiber, S., Meitinger, T., Eriksson, J. G., Salomaa, V., Heikkilä, K., Loehrer, E., Uitterlinden, A. G., Hofman, A., van Duijn, C. M., Cherkas, L., Pedersen, L. M., Stubhaug, A., Nielsen, C. S., Männikkö, M., Mihailov, E., Milani, L., Göbel, H., Esserlind, A.-L., Francke Christensen, A., Folkmann Hansen, T., Werge, T., Kaprio, J., Aromaa, A. J., Raitakari, O., Ikram, M. A., Spector, T., Järvelin, M.-R., Metspalu, A., Kubisch, C., Strachan, D. P., Ferrari, M. D., Belin, A. C., Dichgans, M., Wessman, M., van den Maagdenberg, A. M. J. M., Zwart, J.-A., Boomsma, D. I., Davey Smith, G., Stefansson, K., Eriksson, N., Daly, M. J., Neale, B. M., Olesen, J., Chasman, D. I., Nyholt, D. R., and Palotie, A.
• College/School: College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health
• Journal Name: Nature Communications
• Publisher: Nature Research
• ISSN: 2041-1723
• ISSN (Online): 2041-1723
• Copyright Holders: Copyright © 2020 The Authors
• First Published: First published in Nature Communications 11: 6285
• Publisher Policy: Reproduced under a Creative Commons License