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Basic Science and Pathogenesis.

Timothy H Ciesielski1, Neetesh Pandey2, Farid Rajabli3

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At least 26 late-onset Alzheimer's disease (LOAD) risk loci show recent evolutionary selection. These findings suggest that LOAD etiology and treatment strategies may need to be tailored to different ancestral populations.

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Area of Science:

  • Genetics
  • Evolutionary Biology
  • Neuroscience

Background:

  • Over 70 single nucleotide polymorphisms (SNPs) are associated with late-onset Alzheimer's disease (LOAD).
  • Common LOAD risk alleles may confer early-life benefits, driving natural selection that differs across populations.
  • Investigating selection in LOAD risk variants across ancestries can illuminate population-specific disease etiology.

Purpose of the Study:

  • To test for recent evolutionary selection in LOAD risk loci across 26 global populations.
  • To identify LOAD risk variants under selection in distinct ancestry groups to understand population-specific LOAD etiology.
  • To determine if selection patterns differ across ancestries, implying variations in comorbidity, intervention efficacy, and off-target effects.

Main Methods:

  • Utilized whole-genome sequence data from 2,504 participants in the 1000 Genomes Project.
  • Employed Selscan to calculate genome-wide nSL scores for recent evolutionary selection in 26 populations.
  • Identified top 1% |nSL| sites near LOAD-associated genes and validated findings using ADSP control data.

Main Results:

  • 52 out of 75 LOAD loci showed variants in the top 1% |nSL| in at least two populations.
  • 26 of these loci were validated in corresponding racial/ethnic (R/E) groups using ADSP data.
  • ICA1 was selected in 22 populations and validated across most ADSP R/E groups; pathway analyses revealed distinct biological processes, such as microtubule function selection in Africans.

Conclusions:

  • At least 26 LOAD risk loci exhibit evidence of recent evolutionary selection.
  • Pathway analyses suggest distinct biological functions are under selection across different superpopulations.
  • LOAD etiology, comorbidity, and pre-morbidity patterns may vary by superpopulation, necessitating tailored research and interventions.