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.
Document Type
Article
Publication Date
3-4-2022
Digital Object Identifier (DOI)
https://doi.org/10.1038/s41380-022-01475-0
Repository Citation
Prokopenko, Dmitry; Lee, Sanghan; Hecker, Julian; Mullin, Kristina; Morgan, Sarah; Katsumata, Yuriko; Weiner, Michael W.; Fardo, David W.; Laird, Nan; Bertram, Lars; Hide, Winston; Lange, Cristoph; and Tanzi, Rudolph E., "Region-Based Analysis of Rare Genomic Variants in Whole-Genome Sequencing Datasets Reveal Two Novel Alzheimer’s Disease-Associated Genes: DTNB and DLG2" (2022). Sanders-Brown Center on Aging Faculty Publications. 202.
https://uknowledge.uky.edu/sbcoa_facpub/202
