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Basic Science and Pathogenesis.

Nicholas R Ray1, Ajneesh Kumar1, Brian W Kunkle2

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Summary
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This study reveals PHLPP1 as a shared genetic locus for Alzheimer's disease (AD) and stroke in individuals of African ancestry. These findings suggest common molecular mechanisms underlying both conditions, aiding in understanding their relationship.

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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.