Basic Science and Pathogenesis

Area of Science:

• Neurogenetics
• Cerebrovascular Disease Research
• Alzheimer's Disease Genetics

Background:

• Cerebrovascular disease (CVD) is a known risk factor for Alzheimer's disease (AD).
• The precise molecular mechanisms linking CVD and AD remain unclear.
• This study investigates the genetic correlation between stroke and AD in African ancestry populations.

Purpose of the Study:

• To elucidate the mechanistic relationship between cerebrovascular disease and Alzheimer's disease.
• To examine the genetic correlation between stroke and AD in individuals of African ancestry.

Main Methods:

• Genome-wide association studies (GWAS) data for AD and stroke in African ancestry.
• Genetic covariance analysis using LAVA to estimate local genetic covariance.
• Enhanced Hi-C Capture Analysis (eHiCA) to examine chromatin interactions at identified loci.
• Whole-genome sequencing (WGS) data analysis in an independent cohort.

Main Results:

• A shared genetic locus on chromosome 18q21.33, including the PHLPP1 gene, was identified between AD and stroke (ρ = 0.77, p = 2.41×10⁻⁶).
• Disease-associated haplotypes at PHLPP1 showed coordinated chromatin interactions in brain samples across ancestries and in AD-relevant cell types.
• Variants at PHLPP1 were nominally significant in an independent meta-analysis of African individuals with WGS data (p = 4.56 × 10⁻⁵).

Conclusions:

• PHLPP1 is nominated as a shared genetic locus for AD and stroke in individuals of African ancestry.
• Shared molecular mechanisms between AD and CVD are crucial for understanding these conditions across diverse populations.
• Findings align with previous admixture mapping studies identifying this locus in African Americans.