TY - JOUR
T1 - Cerebral small vessel disease genomics and its implications across the lifespan
AU - International Network against Thrombosis (INVENT) Consortium
AU - International Headache Genomics Consortium (IHGC)
AU - Sargurupremraj, Muralidharan
AU - Suzuki, Hideaki
AU - Jian, Xueqiu
AU - Sarnowski, Chloé
AU - Evans, Tavia E.
AU - Bis, Joshua C.
AU - Eiriksdottir, Gudny
AU - Sakaue, Saori
AU - Terzikhan, Natalie
AU - Habes, Mohamad
AU - Zhao, Wei
AU - Armstrong, Nicola J.
AU - Hofer, Edith
AU - Yanek, Lisa R.
AU - Hagenaars, Saskia P.
AU - Kumar, Rajan B.
AU - van den Akker, Erik B.
AU - McWhirter, Rebekah E.
AU - Trompet, Stella
AU - Mishra, Aniket
AU - Saba, Yasaman
AU - Satizabal, Claudia L.
AU - Beaudet, Gregory
AU - Petit, Laurent
AU - Tsuchida, Ami
AU - Zago, Laure
AU - Schilling, Sabrina
AU - Sigurdsson, Sigurdur
AU - Gottesman, Rebecca F.
AU - Lewis, Cora E.
AU - Aggarwal, Neelum T.
AU - Lopez, Oscar L.
AU - Smith, Jennifer A.
AU - Valdés Hernández, Maria C.
AU - van der Grond, Jeroen
AU - Wright, Margaret J.
AU - Knol, Maria J.
AU - Dörr, Marcus
AU - Thomson, Russell J.
AU - Bordes, Constance
AU - Le Grand, Quentin
AU - Duperron, Marie Gabrielle
AU - Smith, Albert V.
AU - Knopman, David S.
AU - Schreiner, Pamela J.
AU - Evans, Denis A.
AU - Rotter, Jerome I.
AU - Beiser, Alexa S.
AU - Maniega, Susana Muñoz
AU - Hottenga, Jouke Jan
N1 - Publisher Copyright:
© 2020, The Author(s).
PY - 2020/12
Y1 - 2020/12
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/85097295783
U2 - 10.1038/s41467-020-19111-2
DO - 10.1038/s41467-020-19111-2
M3 - Article
C2 - 33293549
AN - SCOPUS:85097295783
SN - 2041-1723
VL - 11
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 6285
ER -