Cerebral small vessel disease genomics and its implications across the lifespan
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.; Lehtimäki, Terho; Eriksson, Johan G. (2020-12)
Nature Communications
6285
https://urn.fi/URN:NBN:fi:tuni-202101181431
Kuvaus
Tiivistelmä
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.
Kokoelmat
- TUNICRIS-julkaisut [19330]