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

Alzheimer’s disease (AD) is a genetically complex disease for which roughly 30 genes have been identified via genome-wide association studies. We attempted to identify rare variants (minor allele frequency <0.01) associated with AD in a region-based, whole genome sequencing (WGS) association study (GSAS) 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 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 test and replicated in case/control samples from the ADSP study (p meta = 4.74×10 −8 ). SKAT analysis revealed region-based association around the discs large homolog 2 ( DLG2 ) gene and replicated in case/control samples from the ADSP study (p meta =1×10 −6 ). Here, in a region-based GSAS of AD we identified two novel AD genes, DLG2 and DTNB , based on association with rare variants.