Key result
Genome-wide association analyses revealed novel significant associations of 35 single-nucleotide polymorphisms outside the chromosome 19q13 region with Alzheimer's disease, most of which were sex-specific.
Why the study?
Despite discovering many susceptibility loci, a major proportion of the genetic variance of Alzheimer's disease remains unexplained.
Meta-Analysis (n=17,480)
Yes
p-value: p=<5E-06
The study identifies novel, sex-specific genetic loci associated with Alzheimer's disease, highlighting the importance of considering sex disparities in the genetic architecture of the disease.
May inform sex-stratified Alzheimer's risk models; extends known loci beyond the 19q13 region.
BACKGROUND: Alzheimer's 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. METHODS: We investigated the genetic architecture of AD in four publicly available independent datasets through genome-wide association, transcriptome-wide association, and gene-based and pathway-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. RESULTS: Our genome-wide association analyses corroborated the associations of several previously detected AD loci and revealed novel significant associations of 35 single-nucleotide polymorphisms (SNPs) outside the chromosome 19q13 region at the suggestive significance level of p < 5E-06. These SNPs were mapped to 21 genes in 19 chromosomal regions. Of these, 17 genes were not associated with AD at genome-wide or suggestive levels of associations by previous genome-wide association studies. Also, the chromosomal regions corresponding to 8 genes did not contain any previously detected AD-associated SNPs with p < 5E-06. Our transcriptome-wide association and gene-based analyses revealed that 26 genes located in 20 chromosomal regions outside chromosome 19q13 had evidence of potential associations with AD at a false discovery rate of 0.05. Of these, 13 genes/regions did not contain any previously AD-associated SNPs at genome-wide or suggestive levels of associations. Most of the newly detected AD-associated SNPs and genes were sex specific, indicating sex disparities in the genetic basis of AD. Also, 7 of 26 pathways that showed evidence of associations with AD in our pathway-bases analyses were significant only in females. CONCLUSIONS: Our 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.
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Nazarian et al. (2019) conducted a meta-analysis in Alzheimer's disease (n=17,480). Genetic variants (SNPs) was evaluated on Association of single-nucleotide polymorphisms (SNPs) with Alzheimer's disease (p=<5E-06). Genome-wide association analyses revealed novel significant associations of 35 single-nucleotide polymorphisms outside the chromosome 19q13 region with Alzheimer's disease, most of which were sex-specific.
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