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Basic Science and Pathogenesis.

Richard Sherva1,2, Henry Bayly3, Rui Zhang2

  • 1Biomedical Genetics, Department of Medicine, Boston University Medical School, Boston, MA, USA.

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This study identified novel dementia risk genes in diverse populations using the Million Veteran Program. Findings highlight genes involved in neuronal development and general dementia pathways, advancing genetic understanding of dementia.

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Area of Science:

  • Genetics
  • Neuroscience
  • Population Health

Background:

  • Growing biobank cohorts increase dementia cases for genetic meta-analyses, identifying more risk variants.
  • Most dementia genetic studies lack diversity, with substantially fewer non-European ancestry participants.
  • The Million Veteran Program (MVP) offers a unique cohort with European (EUR), African (AFR), and Hispanic (HIS) ancestry participants.

Purpose of the Study:

  • To analyze three dementia phenotypes within the MVP cohort.
  • To meta-analyze MVP dementia data with existing public summary statistics.
  • To identify novel dementia risk variants across diverse ancestral groups.

Main Methods:

  • Analyzed Alzheimer's disease and related dementias (ADRD), dementia medication prescriptions, and proxy-reported dementia in MVP.
  • Performed genome-wide association studies (GWAS) within MVP ancestry groups (EUR, AFR, HIS).
  • Generated meta-analyses combining MVP data with public statistics (Bellenguez et al. 2022, Kunkle et al. 2021) for EUR and cross-ancestry analyses.

Main Results:

  • Identified 19 novel genome-wide significant (GWS) regions in EUR, 5 in MVP EUR, and 14 in the meta-analysis.
  • Discovered 11 novel regions in the cross-ancestry meta-analysis.
  • Found two genes (PAX7, PTPRD) unique to AFR and HIS cohorts, previously only observed in HIS.

Conclusions:

  • MVP-specific genes may influence general dementia pathways or have sex-specific effects (stronger in males).
  • Novel genes from EUR and cross-ancestry analyses are implicated in neuronal development, function, and cognitive outcomes.
  • This research enhances the understanding of dementia genetics across diverse ancestries.