This is a 2-year, revised-work scope competitive renewal for the Genetics of Microangiopathic Brain Injury (GMBI) study, initially funded in 2001 as an ancillalY study to the Genetic Epidemiology Network of Arteriopathy (GENOA) and Family Blood Pressure Program. In the initial GMBI grant cycle (2001-2006). we conducted genomewide linkage analyses and candidate gene association analyses to identify genes influencing leukoaraiosis, a heritable measure of ischemic brain injury determined by magnetic resonance imaging (MRI) of subcortical white matter hyperintensity volume in 883 non-Hispanic white and 795 nonHispanic black GMBI-GENOA participants ascertained through sibships with 2 or more members with essential hypertension. The 2?year revised?work scope research plan proposes a functional genomic strategy based on gene expression measurements to identify genetic variants influencing leukoaraiosis and other MRI measures of structural brain injury (cerebral atrophy and ventricular enlargement) associated with risk factors for arteriosclerosis and predictive of stroke and dementia. The power of the proposed approach derives from assessment of functional consequences of genomic variations associated with or linked to MRI measures of structural brain injury.
Aim 1 will determine whether DNA sequence variants previously found to influence MRI measures of structural brain injury may also have functional effects on heritable measures of gene expression in immortalized lymphocytes from 883 white GMBI participants.
Aim 2 will determine whether inter?individual variation in gene expression levels in immortalized lymphocytes, which provide quantitative indices of the heritable, functional effects of multiple DNA sequence variations in a gene region, are associated with MRI measures of structural brain injury in white GMBI participants.

Public Health Relevance

PROJECT SUMMARY/RELEVANCE Understanding relationships between genetic variation and structural measures of brain injury is fundamental to development of more effective, individualized approaches to identification of risk, prevention of disability, and reduction of costs associated with an aging population.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Cardiovascular and Sleep Epidemiology (CASE)
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Gwinn, Katrina
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Mayo Clinic, Rochester
United States
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Ben-Avraham, Dan; Karasik, David; Verghese, Joe et al. (2017) The complex genetics of gait speed: genome-wide meta-analysis approach. Aging (Albany NY) 9:209-246
Windham, B Gwen; Wilkening, Steven R; Lirette, Seth T et al. (2016) Associations Between Inflammation and Physical Function in African Americans and European Americans with Prevalent Cardiovascular Risk Factors. J Am Geriatr Soc 64:1448-55
Mielke, Michelle M; Milic, Natasa M; Weissgerber, Tracey L et al. (2016) Impaired Cognition and Brain Atrophy Decades After Hypertensive Pregnancy Disorders. Circ Cardiovasc Qual Outcomes 9:S70-6
Ibrahim-Verbaas, C A; Bressler, J; Debette, S et al. (2016) GWAS for executive function and processing speed suggests involvement of the CADM2 gene. Mol Psychiatry 21:189-197
Olfson, E; Saccone, N L; Johnson, E O et al. (2016) Rare, low frequency and common coding variants in CHRNA5 and their contribution to nicotine dependence in European and African Americans. Mol Psychiatry 21:601-7
Schmidt, Mike F; Freeman, Kevin B; Windham, Beverly G et al. (2016) Associations Between Serum Inflammatory Markers and Hippocampal Volume in a Community Sample. J Am Geriatr Soc 64:1823-9
Debette, St├ęphanie; Ibrahim Verbaas, Carla A; Bressler, Jan et al. (2015) Genome-wide studies of verbal declarative memory in nondemented older people: the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium. Biol Psychiatry 77:749-63
Verhaaren, Benjamin F J; Debette, St├ęphanie; Bis, Joshua C et al. (2015) Multiethnic genome-wide association study of cerebral white matter hyperintensities on MRI. Circ Cardiovasc Genet 8:398-409
Zhao, Wei; Smith, Jennifer A; Mao, Guangmei et al. (2015) The cis and trans effects of the risk variants of coronary artery disease in the Chr9p21 region. BMC Med Genomics 8:21
Windham, B Gwen; Simpson, Brittany N; Lirette, Seth et al. (2014) Associations between inflammation and cognitive function in African Americans and European Americans. J Am Geriatr Soc 62:2303-10

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