Date Published: January 12, 2019
Publisher: BioMed Central
Author(s): Alireza Nazarian, Anatoliy I. Yashin, Alexander M. Kulminski.
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.
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.
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. 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. The online version of this article (10.1186/s13195-018-0458-8) contains supplementary material, which is available to authorized users.
Alzheimer’s disease (AD) is a slowly progressive neurodegenerative disorder that usually manifests with insidious deterioration of cognitive functions such as memory, language, judgment, and reasoning. Visuospatial deficits and neuropsychiatric symptoms like anxiety, irritability, depression, delusion, and personality changes may occur in the course of the disease, and these are eventually followed by impairment of most daily activities [1, 2]. The median survival is 3.3–11.7 years after disease manifestation . Except for some uncommon autosomal dominant forms, AD is mainly a complex disorder with a polygenic nature [2, 4] that predominantly affects elderly individuals, also known as late-onset AD. It is the most common cause of dementia in the elderly worldwide  and is the sixth leading cause of death in the United States . Age is the main risk factor for AD. The annual incidence increases from 1% at age 65 years to 6–8% after 85 years , and its prevalence increases from 11% to 32% . In addition, AD is more prevalent in females than males [7–10], with their lifetime risk of developing the disease being almost twice that of males . This might be to some extent justified by different life expectancies of males and females. However, Genin et al.  suggested that the age-adjusted penetrance of Apolipoprotein E (APOE) was sex dependent as well. For instance, they found that the lifetime risks for homozygote APOE-ε4 carriers were 51% and 60% in males and females older than 85 years, respectively. The corresponding risks for heterozygote APOE-ε3ε4 carriers were 23% and 30%, respectively . AD is also more severe in females than males . Henderson and Buckwalter  reported that female AD patients had greater impairment of naming task, verbal fluency, and delayed recall compared to male patients. In another study, Barnes et al.  suggested that females were more likely to develop clinical AD compared to males in response to pathology changes (e.g., amyloid beta (Aβ) and neurofibrillary tangles) in the brain. They found that each additional unit of pathology in the brain would increase the odds of overt AD by 20-fold and 3-fold in females and males, respectively . The underlying mechanisms of sex disparity in AD are not fully clear [9, 14]. This may raise the possibility that such sex disparities might be in part due to potential differences in the genetic bases of AD between males and females. Investigating such differences is important, particularly for tailoring more effective medical interventions [14, 15].
The genetic architecture of AD has been widely studied in recent years, and so far more than 60,000 SNPs have been associated with AD with p < 0.05. Of these, 281 SNPs (mapped to 49 genes) and 593 SNPs (mapped to 165 genes) had significant p values at the genome-wide and suggestive levels of associations, respectively . Despite these efforts, a major proportion of h2 of AD has remained unexplained. Exploring the genetic risk factors contributing to AD is highly important from a precision medicine perspective where the goal is to personalize diagnostic and therapeutic interventions. The current study provides further insight into the genetic architecture of AD through GWA, TWA, gene-based, and pathway-based analyses of four independent datasets. These datasets, particularly the LOADFS cohort, were partially used in previous genetic studies of AD [21, 72, 75, 79–87]. In summary, our study revealed significant associations of several SNPs at genome-wide or suggestive levels of significance which were not reported before. Most of the SNPs that were located outside the APOE cluster gene region were not in LD with previously discovered AD-associated polymorphisms that had p < 5E–06 (Table 2). These SNPs were mapped to 21 genes in 19 chromosomal regions. Of these, 8 genes/regions had not been associated with AD in previous GWAS with p < 5E–06. Also, 26 genes located outside the chromosome 19q13 region, and 26 pathways, showed evidence of associations with AD at the FDR level of 0.05 in our TWA, gene-based, and pathway-based analyses. Thirteen of these 26 genes were located in chromosomal regions with no AD-associated SNPs at the genome-wide or suggestive level of significance. Most of the significantly detected SNPs and genes as well as several AD-associated pathways were sex specific, indicating sex disparities in the genetic basis of AD. By detecting a number of novel potential AD-associated SNPs and discovering suggestive associations of several genes and transcripts, our study provides new insight into the genetic architecture of AD. Particularly, identifying sex-specific genetic contributors can advance our understanding of AD pathogenesis. Source: http://doi.org/10.1186/s13195-018-0458-8