Region-based analysis of rare genomic variants in whole-genome sequencing datasets reveal two novel Alzheimer’s disease-associated genes: DTNB and DLG2

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Abstract

Alzheimer’s disease (AD) is a genetically complex disease for which nearly 40 loci have now been identified via genome-wide association studies (GWAS). We attempted to identify groups of rare variants (alternate allele frequency <0.01) associated with AD in a region-based, whole-genome sequencing (WGS) association study (rvGWAS) of two independent AD family datasets (NIMH/NIA; 2247 individuals; 605 families). Employing a sliding window approach across the genome, we identified several regions that achieved association p values <10−6, using the burden test or the SKAT statistic. The genomic region around the dystobrevin beta (DTNB) gene was identified with the burden and SKAT test and replicated in case/control samples from the ADSP study reaching genome-wide significance after meta-analysis (pmeta = 4.74 × 10−8). SKAT analysis also revealed region-based association around the Discs large homolog 2 (DLG2) gene and replicated in case/control samples from the ADSP study (pmeta = 1 × 10−6). In conclusion, in a region-based rvGWAS of AD we identified two novel AD genes, DLG2 and DTNB, based on association with rare variants.

Original languageEnglish
Pages (from-to)1963-1969
Number of pages7
JournalMolecular Psychiatry
Volume27
Issue number4
DOIs
StatePublished - Apr 2022

Bibliographical note

Publisher Copyright:
© 2022, The Author(s).

ASJC Scopus subject areas

  • Psychiatry and Mental health
  • Cellular and Molecular Neuroscience
  • Molecular Biology

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