Cerebral small vessel disease genomics and its implications across the lifespan

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 b...

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Vydané v:	Nature communications Ročník 11; číslo 1; s. 6285 - 18
Hlavní autori:	Sargurupremraj, Muralidharan, Suzuki, Hideaki, Jian, Xueqiu, Sarnowski, Chloé, Evans, Tavia E., Eiriksdottir, Gudny, Sakaue, Saori, Terzikhan, Natalie, Zhao, Wei, Armstrong, Nicola J., Yanek, Lisa R., 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, Schilling, Sabrina, Sigurdsson, Sigurdur, Lewis, Cora E., Lopez, Oscar L., Smith, Jennifer A., Valdés Hernández, Maria C., van der Grond, Jeroen, Wright, Margaret J., Knol, Maria J., Thomson, Russell J., Le Grand, Quentin, Duperron, Marie-Gabrielle, Smith, Albert V., 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, Sidney, Stephen, Turner, Stephen T., Davies, Gail, Thalamuthu, Anbupalam, Völker, Uwe, van Buchem, Mark A., Dupuis, Josée, Bastin, Mark E., 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, Matsuda, Fumihiko, Psaty, Bruce M., Bennett, David A., De Jager, Philip L., Mosley, Thomas H., Sachdev, Perminder S., Schmidt, Reinhold, Evangelou, Evangelos, Trégouët, David-Alexandre, Ikram, Mohammad A., 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
Médium:	Journal Article
Jazyk:	English
Vydavateľské údaje:	London Nature Publishing Group UK 08.12.2020 Nature Publishing Group Nature Portfolio
Predmet:	45/43 631/208/205/2138 692/617/375/599 Adult Aged Aged, 80 and over Alzheimer Disease - epidemiology Alzheimer Disease - genetics Blood pressure Blood vessels Brain Cerebral Small Vessel Diseases - complications Cerebral Small Vessel Diseases - diagnosis Cerebral Small Vessel Diseases - genetics Clinical trials Cognitive science Dementia disorders Diffusion Tensor Imaging Female Gene expression Genetic Loci Genome-Wide Association Study Genomics Health risk assessment Humanities and Social Sciences Humans Hypertension Hypertension - epidemiology Hypertension - genetics Life span Male Medical History Taking Medical imaging Mendelian Randomization Analysis Middle Aged multidisciplinary Neuroimaging Neuroscience Risk analysis Risk Assessment Risk Factors Science Science (multidisciplinary) Stroke - epidemiology Stroke - genetics Substantia alba Therapeutic targets Vascular diseases White Matter - diagnostic imaging Young Adult
ISSN:	2041-1723, 2041-1723
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Popis
Shrnutí:	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. White matter hyperintensities (WMH) are a common brain-imaging feature of cerebral small vessel disease. Here, the authors carry out a GWAS and followup analyses for WMH-volume, implicating several variants with potential for risk stratification and drug targeting.
Bibliografia:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 ObjectType-Undefined-3
ISSN:	2041-1723 2041-1723
DOI:	10.1038/s41467-020-19111-2