| Title: | Cerebral small vessel disease genomics and its implications across the lifespan |
| Journal: | Nature Communications |
| Published: | 8 Dec 2020 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/33293549/ |
| DOI: | https://doi.org/10.1038/s41467-020-19111-2 |
| URL: | https://www.nature.com/articles/s41467-020-19111-2.pdf |
Publication 9314
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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.</p>
116 Authors
- 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 E. McWhirter
- Stella Trompet
- Aniket Mishra
- Yasaman Saba
- Claudia L. Satizabal
- Gregory Beaudet
- Laurent Petit
- Ami Tsuchida
- Laure Zago
- Sabrina Schilling
- Sigurdur Sigurdsson
- Rebecca F. Gottesman
- Cora E. Lewis
- Neelum T. Aggarwal
- Oscar L. Lopez
- Jennifer A. Smith
- Maria C. Valdés Hernández
- Jeroen van der Grond
- Margaret J. Wright
- Maria J. Knol
- Marcus Dörr
- Russell J. 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 S. Beiser
- Susana Muñoz Maniega
- Marian Beekman
- Julian Trollor
- David J. Stott
- Meike W. Vernooij
- Katharina Wittfeld
- Wiro J. Niessen
- Aicha 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
- Evangelos Evangelou
- David-Alexandre Trégouët
- Mohammad A. Ikram
- Wei Wen
- Charles DeCarli
- Velandai K. Srikanth
- J. Wouter Jukema
- Eline P. Slagboom
- Sharon L. R. Kardia
- Yukinori Okada
- Bernard Mazoyer
- Joanna M. Wardlaw
- Paul A. Nyquist
- Karen A. Mather
- Hans J. Grabe
- Helena Schmidt
- Cornelia M. Van Duijn
- Vilmundur Gudnason
- William T. Longstreth
- Lenore J. Launer
- Mark Lathrop
- Sudha Seshadri
- Christophe Tzourio
- Hieab H. Adams
- Paul M. Matthews
- Myriam Fornage
- Stéphanie Debette
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