Cerebral small vessel disease (SVD) encompasses a spectrum of pathologies that affect the small vessels of the brain. Manifestation of SVD includes heterogeneous lesions in the brain parenchyma detectable by magnetic resonance imaging (MRI). In particular, white matter hyperintensities (WMH) are commonly-identified lesions in the elderly brain and are widely recognized as a significant predictor of stroke, dementia, and mortality. Genetic factors and hypertension are major risk factors of SVD and genome-wide association studies have recently identified novel loci for WMH. Yet, the common variants at these loci explain only a fraction of the genetic contribution to the phenotypic variance. There are several possible sources of the residual genetic variance or missing heritability, including rare sequence variation and epigenetic variation. However, the contribution of these two sources of variation to SVD risk and its associated comorbidities has not been widely explored. We hypothesize that the interplay between genotype, epigenotype, and risk factor exposure underlies SVD etiology and propose an integrated analytic framework to identify such relationships. The proposed project will use the resources of the 4 large population-based, prospective cohorts of the Atherosclerosis Risk in Communities study, Cardiovascular Health Study, the Framingham Heart Study and the Rotterdam Study to (1) conduct whole-exome association analyses of MRI-defined cerebral SVD using already-collected whole exome sequence (WES) data on over 5000 participants with a brain MRI; (2) conduct blood methylome association analyses of MRI-defined cerebral SVD; (3) identify novel blood methylome signatures that mediate the causal relationships between MRI-defined SVD and exposure to high blood pressure; and (4) investigate whether the combined information on genetic and epigenetic variation predicts susceptibility to clinical events, including ischemic stroke and dementia.

Public Health Relevance

Cerebral small vessel disease (SVD) manifests itself as lesions in the brain parenchyma detectable by magnetic resonance imaging. These lesions are common in the elderly and have been widely recognized as significant predictors of stroke, dementia, and mortality. There are no effective therapies to reduce the burden of these lesions. Identification of target genes and pathways provides avenues to understanding the molecular pathology of SVD and to developing novel therapeutic and preventive interventions.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS087541-04
Application #
9243322
Study Section
Cardiovascular and Sleep Epidemiology Study Section (CASE)
Program Officer
Koenig, James I
Project Start
2014-04-01
Project End
2019-03-31
Budget Start
2017-04-01
Budget End
2019-03-31
Support Year
4
Fiscal Year
2017
Total Cost
Indirect Cost
Name
University of Texas Health Science Center Houston
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
800771594
City
Houston
State
TX
Country
United States
Zip Code
77030
Jian, Xueqiu; Satizabal, Claudia L; Smith, Albert V et al. (2018) Exome Chip Analysis Identifies Low-Frequency and Rare Variants in MRPL38 for White Matter Hyperintensities on Brain Magnetic Resonance Imaging. Stroke 49:1812-1819
Jian, Xueqiu; Fornage, Myriam (2018) Imaging Endophenotypes of Stroke as a Target for Genetic Studies. Stroke 49:1557-1562
Sims, Rebecca (see original citation for additional authors) (2017) Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease. Nat Genet 49:1373-1384
Dong, Jing; Wyss, Annah; Yang, Jingyun et al. (2017) Genome-Wide Association Analysis of the Sense of Smell in U.S. Older Adults: Identification of Novel Risk Loci in African-Americans and European-Americans. Mol Neurobiol 54:8021-8032
Adams, Hieab H H (see original citation for additional authors) (2016) Novel genetic loci underlying human intracranial volume identified through genome-wide association. Nat Neurosci 19:1569-1582
Hofer, Edith; Cavalieri, Margherita; Bis, Joshua C et al. (2015) White Matter Lesion Progression: Genome-Wide Search for Genetic Influences. Stroke 46:3048-57
Luciano, Michelle; Marioni, Riccardo E; Valdés Hernández, Maria et al. (2015) Structural Brain MRI Trait Polygenic Score Prediction of Cognitive Abilities. Twin Res Hum Genet 18:738-45
Gottesman, Rebecca F; Fornage, Myriam; Knopman, David S et al. (2015) Brain Aging in African-Americans: The Atherosclerosis Risk in Communities (ARIC) Experience. Curr Alzheimer Res 12:607-13
Carty, Cara L; Keene, Keith L; Cheng, Yu-Ching et al. (2015) Meta-Analysis of Genome-Wide Association Studies Identifies Genetic Risk Factors for Stroke in African Americans. Stroke 46:2063-8
Verhaaren, Benjamin F J; Debette, Stéphanie; Bis, Joshua C et al. (2015) Multiethnic genome-wide association study of cerebral white matter hyperintensities on MRI. Circ Cardiovasc Genet 8:398-409

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