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Basic Science and Pathogenesis.

Khine Zin Aung1,2, Xian Wu1,2, Inori Tsuchiya1,2

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This study explored multiallelic variants in brain arteriolosclerosis (B-ASC), a common cause of cognitive decline in the elderly. Novel genetic associations were identified, advancing our understanding of B-ASC pathogenesis.

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Area of Science:

  • Genetics
  • Neuropathology
  • Genomics

Background:

  • Brain arteriolosclerosis (B-ASC) is a common small vessel disease in the elderly, linked to cognitive and motor impairments.
  • Genome-wide association studies (GWAS) have identified single nucleotide polymorphisms (SNPs) associated with B-ASC.
  • Standard GWAS methods often overlook multiallelic variants, necessitating advanced analytical approaches.

Purpose of the Study:

  • To investigate the association between multiallelic variants and autopsy-confirmed B-ASC.
  • To explore the genetic architecture of B-ASC beyond single nucleotide polymorphisms (SNPs).

Main Methods:

  • Utilized whole-genome sequencing (WGS) data from the Alzheimer's Disease Sequencing Project (ADSP).
  • Employed score-based testing within a generalized linear model framework for multiallelic variant analysis.
  • Analyzed autopsy-confirmed B-ASC phenotype data from the National Alzheimer's Coordinating Center (NACC) dataset.

Main Results:

  • Retained 1,388,681 multiallelic variants after quality control.
  • Identified genomic regions and genes (HULC, CCDC3, DCUN1D2) with potential involvement in B-ASC (p < 1x10^-5).
  • These findings suggest novel loci contributing to the genetic basis of B-ASC.

Conclusions:

  • This study highlights the importance of investigating multiallelic variants in B-ASC.
  • Identified potential novel genetic variants associated with B-ASC pathogenesis.
  • Further validation in independent datasets is required to confirm these findings.