AS635 - ERICH-GENE: A genome-wide study of intracerebral hemorrhage

Investigator Names and Contact Information

Chris Anderson

Introduction/Intent

Intracerebral hemorrhage (ICH) is the most severe form of stroke, occurring in >80,000 people in the U.S. each year, with 40-50% mortality. ICH is an acute manifestation of cerebral small vessel disease (CSVD), a prevalent condition that contributes to stroke, depression, gait disorders, vascular cognitive impairment, and Alzheimer’s Disease-Related Dementias. Aside from hypertension control, there are no effective prevention strategies for ICH or CSVD. There are also major health disparities in ICH, with incidence in blacks and Hispanics more than twice that of whites. Novel therapies are critical if we are to reduce the morbidity and mortality of these diseases.

Genome-wide association studies (GWAS) have emerged as an effective strategy for illuminating the underlying processes that lead to common diseases. A crucial lesson has been that inclusion of samples of non-European ancestry in genetic studies improves detection of new therapeutic targets and provides evidence for effects across ancestries. For example, the discovery of loss-of-function variants in PCSK9 in African-Americans led to FDA-approved PCSK9-inhibitors for LDL reduction, and our recent trans-ethnic meta-analysis of ischemic stroke uncovered 22 novel risk loci for functional exploration, 18 of which were strengthened by the trans-ethnic design.

While GWAS of ICH in European-ancestry populations have revealed risk associations at 1q22, 13q34, and APOE, and further associations with ICH volume, outcome, and recurrence, we continue to lag behind other common and debilitating diseases in genetic associations for exploration as therapeutic targets. Further, even among these loci there is evidence of variation in effects across ethnicities. We have identified major differences in the impact of APOE on ICH risk across white, black, and Hispanic populations, at least partially explained by the differential burden of other risk factors in underserved populations. Studies of ICH in diverse populations are therefore sorely needed to 1) evaluate the contribution of genetic risk factors across populations of varying backgrounds, and 2) leverage trans-ethnic meta-analyses to identify novel targets for treatment and prevention.

Our guiding hypothesis is that pooling the largest available sample of well-phenotyped multiethnic ICH patients will permit well-powered GWAS relevant to the US population. The large populations of white, black, and Hispanic ICH cases assembled under the Ethnic/Racial Variations of Intracerebral Hemorrhage (ERICH) study (PI Woo) with existing whole genome sequencing (WGS) through the NHGRI, supplemented by additional samples from the Women’s Health Initiative (WHI) International Stroke Genetics Consortium (ISGC) and other initiatives represents a golden opportunity to advance the search for novel genetic associations in a diverse population at the lowest cost. Additionally, the imaging and outcome biomarkers available on selected ICH cases will permit concomitant genetic analyses of ICH-related phenotypes, which promises to improve our understanding of genetic mechanisms that contribute to CSVD-related morbidity in the aging U.S. population.

Aim 1: Perform a well-powered GWAS of ICH risk, outcome, and CSVD imaging phenotypes in a multiethnic dataset. We will perform genome-wide genotyping in 5,600 ICH patients from centers across the ISGC and combine the results with WGS data from 3,800 ICH patients from ERICH and WHI and 20,000 control subjects matched by race and ethnicity. We will harmonize genotypes and phenotypes between studies and perform a GWAS of ICH risk, outcome, and imaging phenotypes followed by trans-ethnic meta-analyses with an additional 15,000 previously-genotyped ICH cases and 500,000 controls from the ISGC and worldwide biobanks.

Aim 2: Identify genetic risk factors for ICH that vary in effect by sex, race, and ethnicity. We will perform stratified and interaction analyses examining sex- and ancestry-specific genetic risk factors for ICH to better understand pathophysiologic mechanisms unique to these populations. Further, based on our prior observations, we will test for interactions between clinical and environmental health exposures such as hypertension and genetic risk factors for ICH using propensity matching and polygenic risk modeling.

Aim 3: Develop a data sharing platform incorporating whole genome sequencing and neuroimaging data. We have previously developed the Cerebrovascular Disease Knowledge Portal, an online resource for sharing of GWAS data for stroke. We will build new capabilities into the portal to allow WGS and neuroimaging phenotypes curated under this proposal to be maximally and usefully shared with stroke researchers worldwide.

Our ultimate goal is to reduce the risk and severity of ICH and limit associated CSVD comorbidities. Completion of these aims will directly advance the search for innovative approaches to treat and prevent ICH and CSVD across broad and representative populations, through the identification of genetic risk factors impacting ICH risk, CSVD imaging biomarkers, and outcomes in a large and multi-ethnic dataset. With the increasing availability of WGS data concurrent with the completion of these specific aims, ICH risk loci discovered through this proposal will be ripe for functional exploration using bioinformatic annotation and gene editing to delineate their biological mechanisms and determine suitability for drug development or incorporation into risk stratification approaches.