Genetics of Frontotemporal Degeneration in Diverse Populations
Abstract
Frontotemporal dementia (FTD) is the second most common dementia at early onset age after Alzheimer’s disease (AD): 10%-20% before 65 years or ~5% of all patients with dementia. Active-duty military and veterans may have an increased risk of developing dementia due to specific exposures they encounter(ed) while on duty, such as traumatic brain injury, depression, post-traumatic stress disorder in addition to normal risk factors affecting the general population. Additionally, dementia occurs more frequently in African Americans (AA) and Hispanics (HI) versus non-Hispanics whites (NHW). Currently there are more than 59 million (18.3%) US residents who identify as HI or Latino and more than 43 million as Black or AA (13.5%) in the US overall. While approximately 12% of active duty and 7% of veterans identified as HI currently, these numbers are expected to increase by another 7% by 2043, indicating military personnel will have a higher percentage HI than the general populations at that time. Taken together, these data suggest a higher dementia rate in the active-duty or veteran population compared to the general population. Research into the genetic variants causing or increasing risk for FTD has identified several genes contributing to FTD development: MAPT, VCP, CHMP2B, GRN, C9orf72, and TBK1. However, variants in these genes are only found in a small percentage of FTD patients (~20%). Additionally, the vast majority of research has been done in NHW populations, indicating a clear gap in knowledge on genetic variants causing disease in FTD overall, but in diverse populations especially. HI (and AA) are admixed populations, indicating they have mixed backgrounds from European, African, and/or Amerindian ancestries. Also their genetic make-up is a mixture of these origins. The variants we identify in HI participants can thus be located on any of these backgrounds. Genetic information in these backgrounds (i.e., the area directly around a variant) can influence its impact on disease, with recent major example in AD where APOEe4 is a major risk factor but the associated risk is >3x larger for APOEe4 on the European background than APOEe4 on the African background. Therefore, it is important to pinpoint which background the identified variant(s) are located on to fully characterize their impact in disease. This admixture in HI also indicates that results from this study can be informative for any population harboring any of these ancestries: HI, NHW, African (American), and Amerindian populations. Besides the different effect of variants dependent on their background described above, recent research in AD also identified variants specific to the African background (i.e., ABCA7 40bp deletion). These different variant or variants effects specific to certain population groups support the notion that research in these diverse populations is necessary to identify and understand all disease variants and their implication in disease. Identification of disease variants helps with diagnoses in new patients and helps with identification of affected biological processes that could potentially be returned to normal with treatments in the future. Therefore, the underrepresentation of HI (and AA) in genetic research represents a major source of health disparity as this will lead to reduced diagnoses due to lack of knowledge on causal genetic variants in these groups and reduced benefit in the future from treatments targeting mechanisms affected by the variants. Therefore, the overall goal of this proposal on FTD will address a specific Area of Encouragement: to identify and characterize genetic factors and networks contributing to FTD in the HI population. We hypothesize that the known variants the field has identified in NHW FTD patients are not necessarily a major cause of disease in HI and AA patients, but that variants underlying disease in HI could originate from European, African, or Amerindian ancestors. We will therefore cr
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110438
Entities
People
- Margaret A. Pericak-Vance
Organizations
- United States Army
- University of Miami