Genome-wide analysis of genetic predisposition to Alzheimer’s disease and related sex-disparities

BackgroundAlzheimers disease (AD) is the most common cause of dementia in the elderly and the sixth leading cause of death in the United States. AD is mainly considered a complex disorder with polygenic inheritance. Despite discovering many susceptibility loci, a major proportion of AD genetic variance remains to be explained.\n\nMethodsWe investigated the genetic architecture of AD in four publicly available independent datasets through genome-wide association, transcriptome-wide association, and gene-based analyses. To explore differences in the genetic basis of AD between males and females, analyses were performed on three samples in each dataset: males and females combined, only males, or only females.\n\nResultsOur genome-wide association analyses corroborated the associations of several previously detected AD loci and revealed novel significant associations of 54 single-nucleotide polymorphisms (SNPs) at a p-value of < 5E-06. In addition, 23 genes located outside the chromosome 19q13 region showed suggestive associations with AD at a false discovery rate of 0.05 in transcriptome-wide association and gene-based analyses. Most of the newly detected AD-associated SNPs and genes were sex specific, indicating sex disparities in the genetic basis of AD.\n\nConclusionsOur findings, particularly the newly discovered sex-specific genetic contributors, provide novel insight into the genetic architecture of AD and can advance our understanding of its pathogenesis.