Stroke is the third leading cause of death and the leading cause of adult disability in the United States. More adults are affected by stroke each year than Alzheimer?s disease, multiple sclerosis, amyotrophic lateral sclerosis or Parkinson?s disease. Intracerebral hemorrhage (ICH) represents the most severe subtype of stroke. An estimated 40-50% of ICH victims will die and more than 80% of survivors remain disabled. Patients with ICH share histopathological features with other forms of cerebral small vessel disease (CSVD) caused by hypertension and cerebral amyloid angiopathy. CSVD is a key component of progressive neurologic decline in Alzheimer?s disease and vascular dementia, and nearly half of ICH survivors develop dementia within 4 years. Our investigators have previously collaborated to publish the largest genome wide association study of ICH with ~1500 cases, which identified novel genetic factors that have since gone on to be replicated in CSVD phenotypes including white matter hyperintensity and small vessel stroke. With greater sample size, we will uncover additional risk factors for ICH and through those mechanisms, Alzheimer?s and vascular dementias. The Ethnic/Racial Variations of Intracerebral Hemorrhage (ERICH) study originally recruited over 3000 cases of spontaneous hemorrhage with equal power among white, black and Hispanic cases. The study design begins with the philosophy that both ethnicity-specific and non-specific risk factors for ICH may exist, and numerous ERICH publications support this. We propose to combine additional ICH cases from around the world to maximize the power of our study to identify novel genetic variants across ethnicities. We have identified over 21,000 cases that have either completed genotyping or have samples available to assess genetic risk of ICH. However, the critical first step is to perform careful phenotype harmonization, specifically in location of hemorrhage which stratifies patients clinically, histopathologically, and genetically. Different studies have used different location definitions which if not harmonized will limit study power due to case misclassification. We have previously performed phenotype harmonization across our two centers for both ICH case status and location in >5,000 cases across 3 NIH-funded studies. We intend to complete harmonization on cases with available data, and expand harmonization to related imaging CSVD phenotypes and clinical outcomes. Next, we will combine genomic data to create polygenic risk scores (PRS) to stratify cumulative genetic risk of ICH at the individual level, which may provide a near-term opportunity to leverage genomic association data to improve clinical care. Finally, we will maximally share all association results and phentoypes through the Cerebrovascular Disease Knowledge Portal, a freely-accessible on-line collaborative resource established with NINDS support. If successful, we will have identified risk factors for ICH, subtypes by location and across CSVD neuroimaging features, which will be valuable as targets for rational therapeutic development. We will also have built PRS for ICH risk and outcome, as a tool to stratify individuals by ICH risk and provide prognostic information on outcomes.

Public Health Relevance

This proposal gathers cases of brain hemorrhage from around the world to identify the genetic factors that either cause or protect people from brain hemorrhage. The larger the sample size, the greater the power of the study and the investigators plan to increase the analysis from the current largest of roughly 1,500 cases to over 20,000 cases of brain hemorrhage. Specific ethnic groups may be particularly susceptible to brain hemorrhage and our study focuses on these important differences by ethnicity.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project--Cooperative Agreements (U01)
Project #
2U01NS069763-06A1
Application #
10069719
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Koenig, James I
Project Start
2010-08-01
Project End
2025-06-30
Budget Start
2020-09-01
Budget End
2021-06-30
Support Year
6
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of Cincinnati
Department
Neurology
Type
Schools of Medicine
DUNS #
041064767
City
Cincinnati
State
OH
Country
United States
Zip Code
45221
Ormseth, Cora H; Falcone, Guido J; Jasak, Sara D et al. (2018) Minority Patients are Less Likely to Undergo Withdrawal of Care After Spontaneous Intracerebral Hemorrhage. Neurocrit Care 29:419-425
Murphy, Meredith P; Kuramatsu, Joji B; Leasure, Audrey et al. (2018) Cardioembolic Stroke Risk and Recovery After Anticoagulation-Related Intracerebral Hemorrhage. Stroke 49:2652-2658
Marini, Sandro; Lena, Umme K; Crawford, Katherine M et al. (2018) Comparison of Genetic and Self-Identified Ancestry in Modeling Intracerebral Hemorrhage Risk. Front Neurol 9:514
Marini, Sandro; Devan, William J; Radmanesh, Farid et al. (2018) 17p12 Influences Hematoma Volume and Outcome in Spontaneous Intracerebral Hemorrhage. Stroke 49:1618-1625
Shah, Manan; Birnbaum, Lee; Rasmussen, Jennifer et al. (2018) Effect of Hyperosmolar Therapy on Outcome Following Spontaneous Intracerebral Hemorrhage: Ethnic/Racial Variations of Intracerebral Hemorrhage (ERICH) Study. J Stroke Cerebrovasc Dis 27:1061-1067
Biffi, Alessandro; Kuramatsu, Joji B; Leasure, Audrey et al. (2017) Oral Anticoagulation and Functional Outcome after Intracerebral Hemorrhage. Ann Neurol 82:755-765
Siddiqui, Fazeel M; Langefeld, Carl D; Moomaw, Charles J et al. (2017) Use of Statins and Outcomes in Intracerebral Hemorrhage Patients. Stroke 48:2098-2104
Woo, Daniel; Debette, Stephanie; Anderson, Christopher (2017) 20th Workshop of the International Stroke Genetics Consortium, November 3-4, 2016, Milan, Italy: 2016.036 ISGC research priorities. Neurol Genet 3:S12-S18
Anderson, Christopher D; Falcone, Guido J; Phuah, Chia-Ling et al. (2016) Genetic variants in CETP increase risk of intracerebral hemorrhage. Ann Neurol 80:730-740
Woo, Daniel; Kruger, Andrew J; Sekar, Padmini et al. (2016) Incontinence and gait disturbance after intraventricular extension of intracerebral hemorrhage. Neurology 86:905-11

Showing the most recent 10 out of 32 publications