Clonal Hematopoiesis in NIAGADS

Approximately 15-20% of people age 70 or older carry a cancer-associated mutation in a substantial proportion of their blood cells, even though the vast majority do not have cancer. This condition has been termed Clonal Hematopoiesis of Indeterminate Potential (CHIP). Past research has demonstrated that CHIP is associated with an increased risk of both all-cause mortality and several age-associated diseases, such as atherosclerotic cardiovascular disease. Using data from TOPMed, we found a surprising correlation: after controlling for competing risks, such as death, age, sex, and APOE genotype, CHIP is associated with protection from AD and AD-related pathologies, and that the degree of protection is proportional to the size of the mutant clone. We would like to improve our understanding of this phenomenon by leveraging the richly annotated whole genome (WGS) and whole exome sequencing (WES) datasets provided by the NIAGADs under the Alzheimer’s Disease Sequencing Project (ADSP). Understanding of this phenomenon could lead to possible treatments and greater ability to predict who will suffer from AD and its related pathologies.
The NIAGADs has already performed the screening, recruitment, consent, and specimen collection. We are requesting access to datasets that include de-identified phenotypic and genetic information from both healthy controls and patients with AD and AD-related pathologies, specifically Dementia and Frontotemporal Dementia. We plan to control for and examine the following phenotypic characteristics: presence or absence of diagnosed neurological disease, age of disease onset (or age at the first visit for control groups), age at specifimen collection, sex, ethnic origin, and measures of cognitive and clinical decline. These phenotypes will be evaluated against genetic information (WES, WGS, single-nucleotide polymorphisms, and polygenic risk scores). Specifically, we plan to use mutation callers in order to identify somatic mutations, such as mutect or varscan (from the WES data, etc.).

Approximately 15-20% of people age 70 or older carry a cancer-associated mutation in a substantial proportion of their blood cells, even though the vast majority do not have cancer. This condition has been termed Clonal Hematopoiesis of Indeterminate Potential (CHIP). Past research has demonstrated that CHIP is associated with an increased risk of both all-cause mortality and several age-associated diseases, such as atherosclerotic cardiovascular disease. Using data from TOPMED and Alzheimer’s Disease (AD) Sequencing Project, we found a surprising correlation: CHIP is associated with protection from AD and AD-related pathologies, and that the degree of protection is proportional to the size of the mutant clone. We would like to improve our understanding of this phenomenon by leveraging the richly annotated whole genome and whole exome sequencing datasets provided by the NIAGADs to replicate this association. Understanding of this phenomenon could lead to possible treatments and greater understanding of individual AD risk.