Genome-wide analysis of genetic predisposition to Alzheimer’s disease and related sex disparities
Abstract 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 ge...
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| Format: | Article |
| Language: | English |
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BMC
2019-01-01
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| Series: | Alzheimer’s Research & Therapy |
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| Online Access: | http://link.springer.com/article/10.1186/s13195-018-0458-8 |
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| author | Alireza Nazarian Anatoliy I. Yashin Alexander M. Kulminski |
| author_facet | Alireza Nazarian Anatoliy I. Yashin Alexander M. Kulminski |
| author_sort | Alireza Nazarian |
| collection | DOAJ |
| description | Abstract 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. |
| first_indexed | 2024-12-12T07:20:20Z |
| format | Article |
| id | doaj.art-0c7ad387e3fe45b38c0b5445cb52460f |
| institution | Directory Open Access Journal |
| issn | 1758-9193 |
| language | English |
| last_indexed | 2024-12-12T07:20:20Z |
| publishDate | 2019-01-01 |
| publisher | BMC |
| record_format | Article |
| series | Alzheimer’s Research & Therapy |
| spelling | doaj.art-0c7ad387e3fe45b38c0b5445cb52460f2022-12-22T00:33:24ZengBMCAlzheimer’s Research & Therapy1758-91932019-01-0111112110.1186/s13195-018-0458-8Genome-wide analysis of genetic predisposition to Alzheimer’s disease and related sex disparitiesAlireza Nazarian0Anatoliy I. Yashin1Alexander M. Kulminski2Biodemography of Aging Research Unit, Social Science Research Institute, Duke UniversityBiodemography of Aging Research Unit, Social Science Research Institute, Duke UniversityBiodemography of Aging Research Unit, Social Science Research Institute, Duke UniversityAbstract 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.http://link.springer.com/article/10.1186/s13195-018-0458-8Alzheimer’s diseaseSex disparitiesGenome-wide association studyMeta-analysisGene-based analysis |
| spellingShingle | Alireza Nazarian Anatoliy I. Yashin Alexander M. Kulminski Genome-wide analysis of genetic predisposition to Alzheimer’s disease and related sex disparities Alzheimer’s Research & Therapy Alzheimer’s disease Sex disparities Genome-wide association study Meta-analysis Gene-based analysis |
| title | Genome-wide analysis of genetic predisposition to Alzheimer’s disease and related sex disparities |
| title_full | Genome-wide analysis of genetic predisposition to Alzheimer’s disease and related sex disparities |
| title_fullStr | Genome-wide analysis of genetic predisposition to Alzheimer’s disease and related sex disparities |
| title_full_unstemmed | Genome-wide analysis of genetic predisposition to Alzheimer’s disease and related sex disparities |
| title_short | Genome-wide analysis of genetic predisposition to Alzheimer’s disease and related sex disparities |
| title_sort | genome wide analysis of genetic predisposition to alzheimer s disease and related sex disparities |
| topic | Alzheimer’s disease Sex disparities Genome-wide association study Meta-analysis Gene-based analysis |
| url | http://link.springer.com/article/10.1186/s13195-018-0458-8 |
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