Dataset Information

Cerebral small vessel disease genomics and its implications across the lifespan.

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.

SUBMITTER: Sargurupremraj M

PROVIDER: S-EPMC7722866 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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Cerebral small vessel disease genomics and its implications across the lifespan.

Sargurupremraj Muralidharan M Suzuki Hideaki H Jian Xueqiu X Sarnowski Chloé C Evans Tavia E TE Bis Joshua C JC Eiriksdottir Gudny G Sakaue Saori S Terzikhan Natalie N Habes Mohamad M Zhao Wei W Armstrong Nicola J NJ Hofer Edith E Yanek Lisa R LR Hagenaars Saskia P SP Kumar Rajan B RB van den Akker Erik B EB McWhirter Rebekah E RE Trompet Stella S Mishra Aniket A Saba Yasaman Y Satizabal Claudia L CL Beaudet Gregory G Petit Laurent L Tsuchida Ami A Zago Laure L Schilling Sabrina S Sigurdsson Sigurdur S Gottesman Rebecca F RF Lewis Cora E CE Aggarwal Neelum T NT Lopez Oscar L OL Smith Jennifer A JA Valdés Hernández Maria C MC van der Grond Jeroen J Wright Margaret J MJ Knol Maria J MJ Dörr Marcus M Thomson Russell J RJ Bordes Constance C Le Grand Quentin Q Duperron Marie-Gabrielle MG Smith Albert V AV Knopman David S DS Schreiner Pamela J PJ Evans Denis A DA Rotter Jerome I JI Beiser Alexa S AS Maniega Susana Muñoz SM Beekman Marian M Trollor Julian J Stott David J DJ Vernooij Meike W MW Wittfeld Katharina K Niessen Wiro J WJ Soumaré Aicha A Boerwinkle Eric E Sidney Stephen S Turner Stephen T ST Davies Gail G Thalamuthu Anbupalam A Völker Uwe U van Buchem Mark A MA Bryan R Nick RN Dupuis Josée J Bastin Mark E ME Ames David D Teumer Alexander A Amouyel Philippe P Kwok John B JB Bülow Robin R Deary Ian J IJ Schofield Peter R PR Brodaty Henry H Jiang Jiyang J Tabara Yasuharu Y Setoh Kazuya K Miyamoto Susumu S Yoshida Kazumichi K Nagata Manabu M Kamatani Yoichiro Y Matsuda Fumihiko F Psaty Bruce M BM Bennett David A DA De Jager Philip L PL Mosley Thomas H TH Sachdev Perminder S PS Schmidt Reinhold R Warren Helen R HR Evangelou Evangelos E Trégouët David-Alexandre DA Ikram Mohammad A MA Wen Wei W DeCarli Charles C Srikanth Velandai K VK Jukema J Wouter JW Slagboom Eline P EP Kardia Sharon L R SLR Okada Yukinori Y Mazoyer Bernard B Wardlaw Joanna M JM Nyquist Paul A PA Mather Karen A KA Grabe Hans J HJ Schmidt Helena H Van Duijn Cornelia M CM Gudnason Vilmundur V Longstreth William T WT Launer Lenore J LJ Lathrop Mark M Seshadri Sudha S Tzourio Christophe C Adams Hieab H HH Matthews Paul M PM Fornage Myriam M Debette Stéphanie S

Nature communications 20201208 1

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 imp ...[more]

PMID: 33293549

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Project description:Cerebral small vessel disease (cSVD) is a leading cause of stroke and dementia. Genetic risk loci for white matter hyperintensities (WMH), the most common MRI-marker of cSVD in older age, were recently shown to be significantly associated with white matter (WM) microstructure on diffusion tensor imaging (signal-based) in young adults. To provide new insights into these early changes in WM microstructure and their relation with cSVD, we sought to explore the genetic underpinnings of cutting-edge tissue-based diffusion imaging markers across the adult lifespan. We conducted a genome-wide association study of neurite orientation dispersion and density imaging (NODDI) markers in young adults (i-Share study: N = 1 758, (mean[range]) 22.1[18-35] years), with follow-up in young middle-aged (Rhineland Study: N = 714, 35.2[30-40] years) and late middle-aged to older individuals (UK Biobank: N = 33 224, 64.3[45-82] years). We identified 21 loci associated with NODDI markers across brain regions in young adults. The most robust association, replicated in both follow-up cohorts, was with Neurite Density Index (NDI) at chr5q14.3, a known WMH locus in VCAN. Two additional loci were replicated in UK Biobank, at chr17q21.2 with NDI, and chr19q13.12 with Orientation Dispersion Index (ODI). Transcriptome-wide association studies showed associations of STAT3 expression in arterial and adipose tissue (chr17q21.2) with NDI, and of several genes at chr19q13.12 with ODI. Genetic susceptibility to larger WMH volume, but not to vascular risk factors, was significantly associated with decreased NDI in young adults, especially in regions known to harbor WMH in older age. Individually, seven of 25 known WMH risk loci were associated with NDI in young adults. In conclusion, we identified multiple novel genetic risk loci associated with NODDI markers, particularly NDI, in early adulthood. These point to possible early-life mechanisms underlying cSVD and to processes involving remyelination, neurodevelopment and neurodegeneration, with a potential for novel approaches to prevention.

Project description:Background and Objective: Studies on relations between arterial stiffness and full spectrum of radiological features of cerebral small vessel disease (CSVD) are scarce. We aim to investigate the association of arterial stiffness with lacunes, white matter hyperintensities (WMH), microbleeds (CMBs), dilated perivascular spaces (PVS), and brain atrophy in a community-based sample. Methods: A total of 953 participants (55.7 ± 9.4 years) who underwent brachial-ankle pulse wave velocity (baPWV) and brain magnetic resonance imaging were included. Lacunes, CMBs, and PVS were visually rated. Brain structure and WMH were automatically segmented. Brain parenchyma fraction (BPF), a surrogate index of brain atrophy, was calculated as a ratio of brain parenchyma volume to total intracranial volume. Multivariable logistic and linear regressions were used to investigate the associations between baPWV and CSVD. Subsequently, we explored these associations in strata of age. Results: Increased baPWV was associated with severe PVS in white matter (OR, 1.09; 95%CI, 1.01-1.17; p = 0.022), larger WMH volume (β, 0.08; 95%CI, 0.04-0.12; p < 0.001), lower BPF (β, -0.09; 95%CI, -0.15- -0.03; p = 0.007), and marginally associated with strictly lobar CMBs (OR, 1.11; 95%CI, 1.00-1.23; p = 0.055), but not with lacunes. WMH volume mediated the relation between baPWV and BPF. In age subgroup analysis, the association of baPWV with PVS in white matter was stronger among those aged <55 years, whereas the association with brain atrophy was more prominent among those aged ≥55 years. Increased baPWV was associated with larger WMH volume in both younger and older individuals. Conclusions: Increased arterial stiffness was associated with most of imaging markers of CSVD, including PVS in white matter, larger WMH volume, strictly lobar CMBs, and brain atrophy, but not lacunes. The mechanisms underlying these associations and their potential clinical significances warrant further investigations.

Dataset Information

Cerebral small vessel disease genomics and its implications across the lifespan.

Publications

Cerebral small vessel disease genomics and its implications across the lifespan.

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