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Basic Science and Pathogenesis.

Liyong Wang1, Wanying Xu2, Maria C Robayo1

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Summary
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European ancestry shows stronger APOE gene interactions, potentially explaining higher Alzheimer's risk. African ancestry suppresses these interactions, revealing ancestry-specific regulatory mechanisms for Alzheimer's disease.

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Area of Science:

  • Genomics
  • Neuroscience
  • Epigenetics

Background:

  • The APOEε4 allele is a major genetic risk factor for Alzheimer's disease (AD).
  • APOEε4's effect size varies across ancestral populations, being larger in Non-Hispanic Whites than African Americans.
  • Local ancestry (LA) around APOE influences genetic risk and gene expression, with European (EU) LA associated with higher risk and expression than African (AF) LA.

Purpose of the Study:

  • To investigate the 3D genome structure at the APOE locus across different ancestral backgrounds.
  • To examine how chromatin interactions at APOE differ between European and African local ancestry.

Main Methods:

  • Utilized Enhanced Hi-C Capture Analysis (eHiCA) on frontal cortex and iPSC-derived microglia (iMGLs).
  • Analyzed samples from ε4/ε4 carriers with homozygous African (AF) and European (EU) LA at APOE.
  • Processed Hi-C data using HiCorr and DeepLoop for enhanced chromatin interaction mapping.

Main Results:

  • Observed ancestry-biased chromatin interactions at the APOE locus in frontal cortex and iMGLs.
  • EU LA exhibited prominent long-range chromatin interactions (190 kb and 440 kb downstream of APOE) not seen in AF LA.
  • AF LA showed suppressed long-range interactions, with only a short-range interaction present in both ancestries.

Conclusions:

  • The EU genome displays stronger and more numerous chromatin interactions at APOE compared to the AF genome.
  • These interactions correlate with increased chromatin accessibility in EU LA, potentially explaining elevated APOEε4 expression in EU brains.
  • eHiCA identified ancestry-biased chromatin interactions, offering insights into AD regulatory mechanisms and the broader AD regulatory landscape.