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.
|Number of pages||7|
|State||Published - Apr 2022|
Bibliographical noteFunding Information:
This work was supported by Cure Alzheimer’s Fund, JPB Foundation and NIH R56AG057191 (DWF and YK). The computations in this paper were run in part on the FASRC Cannon cluster supported by the FAS Division of Science Research Computing Group at Harvard University with support from John Morrissey and in part on computers provided by Dell HPC Research Computing Solutions with support by Glen Otero. The funding body has no role in the design of the study and collection, analysis, and interpretation of data and in writing the manuscript. Please refer to the Supplementary Note for full acknowledgements.
© 2022, The Author(s).
ASJC Scopus subject areas
- Psychiatry and Mental health
- Cellular and Molecular Neuroscience
- Molecular Biology