Genome-Wide Association and Mechanistic Studies Indicate That Immune Response Contributes to Alzheimer’s Disease Development
Alzheimer’s disease (AD) is the most common cause of dementia. Although genome-wide association study (GWAS) have reported hundreds of single-nucleotide polymorphisms (SNPs) and genes linked to AD, the mechanisms about how these SNPs modulate the development of AD remain largely unknown. In this stu...
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Frontiers Media S.A.
2018-09-01
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| Series: | Frontiers in Genetics |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fgene.2018.00410/full |
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| author | Changan Liu Jacqueline Chyr Weiling Zhao Yungang Xu Zhiwei Ji Hua Tan Claudio Soto Xiaobo Zhou for the Alzheimer’s Disease Neuroimaging Initiative |
| author_facet | Changan Liu Jacqueline Chyr Weiling Zhao Yungang Xu Zhiwei Ji Hua Tan Claudio Soto Xiaobo Zhou for the Alzheimer’s Disease Neuroimaging Initiative |
| author_sort | Changan Liu |
| collection | DOAJ |
| description | Alzheimer’s disease (AD) is the most common cause of dementia. Although genome-wide association study (GWAS) have reported hundreds of single-nucleotide polymorphisms (SNPs) and genes linked to AD, the mechanisms about how these SNPs modulate the development of AD remain largely unknown. In this study, we performed GWAS for three traits in cerebrospinal fluid (CSF) and one clinical trait in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort. Our analysis identified five most significant AD related SNPs (FDR < 0.05) within or proximal to APOE, APOC1, and TOMM40. One of the SNPs was co-inherited with APOE allele 4, which is the most important genetic risk factor for AD. Three of the five SNPs were located in promoter or enhancer regions, and transcription factor (TF) binding affinity calculations showed dramatic changes (| Log2FC| > 2) of three TFs (PLAG1, RREB1, and ZBTB33) for two motifs containing SNPs rs2075650 and rs157580. In addition, our GWAS showed that both rs2075650 and rs157580 were significantly associated with the poliovirus receptor-related 2 (PVRL2) gene (FDR < 0.25), which is involved in spreading of herpes simplex virus (HSV). The altered regulation of PVRL2 may increase the susceptibility AD patients to HSV and other virus infections of the brain. Our work suggests that AD is a type of immune disorder driven by viral or microbial infections of the brain during aging. |
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| language | English |
| last_indexed | 2024-12-20T19:43:41Z |
| publishDate | 2018-09-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Genetics |
| spelling | doaj.art-ade84beb7ed743f59e86bec2e1ed0a172022-12-21T19:28:27ZengFrontiers Media S.A.Frontiers in Genetics1664-80212018-09-01910.3389/fgene.2018.00410384804Genome-Wide Association and Mechanistic Studies Indicate That Immune Response Contributes to Alzheimer’s Disease DevelopmentChangan Liu0Jacqueline Chyr1Weiling Zhao2Yungang Xu3Zhiwei Ji4Hua Tan5Claudio Soto6Xiaobo Zhou7for the Alzheimer’s Disease Neuroimaging InitiativeSchool of Biomedical Informatics, The University of Texas Health Science Center at Houston, Houston, TX, United StatesSchool of Biomedical Informatics, The University of Texas Health Science Center at Houston, Houston, TX, United StatesSchool of Biomedical Informatics, The University of Texas Health Science Center at Houston, Houston, TX, United StatesSchool of Biomedical Informatics, The University of Texas Health Science Center at Houston, Houston, TX, United StatesSchool of Biomedical Informatics, The University of Texas Health Science Center at Houston, Houston, TX, United StatesSchool of Biomedical Informatics, The University of Texas Health Science Center at Houston, Houston, TX, United StatesDepartment of Neurology, The George and Cynthia W Mitchell Center for Alzheimer’s Disease and Other Brain Related Illnesses, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, United StatesSchool of Biomedical Informatics, The University of Texas Health Science Center at Houston, Houston, TX, United StatesAlzheimer’s disease (AD) is the most common cause of dementia. Although genome-wide association study (GWAS) have reported hundreds of single-nucleotide polymorphisms (SNPs) and genes linked to AD, the mechanisms about how these SNPs modulate the development of AD remain largely unknown. In this study, we performed GWAS for three traits in cerebrospinal fluid (CSF) and one clinical trait in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort. Our analysis identified five most significant AD related SNPs (FDR < 0.05) within or proximal to APOE, APOC1, and TOMM40. One of the SNPs was co-inherited with APOE allele 4, which is the most important genetic risk factor for AD. Three of the five SNPs were located in promoter or enhancer regions, and transcription factor (TF) binding affinity calculations showed dramatic changes (| Log2FC| > 2) of three TFs (PLAG1, RREB1, and ZBTB33) for two motifs containing SNPs rs2075650 and rs157580. In addition, our GWAS showed that both rs2075650 and rs157580 were significantly associated with the poliovirus receptor-related 2 (PVRL2) gene (FDR < 0.25), which is involved in spreading of herpes simplex virus (HSV). The altered regulation of PVRL2 may increase the susceptibility AD patients to HSV and other virus infections of the brain. Our work suggests that AD is a type of immune disorder driven by viral or microbial infections of the brain during aging.https://www.frontiersin.org/article/10.3389/fgene.2018.00410/fullAlzheimer’s diseaseGWASSNPmechanismtranscription factorbinding affinity |
| spellingShingle | Changan Liu Jacqueline Chyr Weiling Zhao Yungang Xu Zhiwei Ji Hua Tan Claudio Soto Xiaobo Zhou for the Alzheimer’s Disease Neuroimaging Initiative Genome-Wide Association and Mechanistic Studies Indicate That Immune Response Contributes to Alzheimer’s Disease Development Frontiers in Genetics Alzheimer’s disease GWAS SNP mechanism transcription factor binding affinity |
| title | Genome-Wide Association and Mechanistic Studies Indicate That Immune Response Contributes to Alzheimer’s Disease Development |
| title_full | Genome-Wide Association and Mechanistic Studies Indicate That Immune Response Contributes to Alzheimer’s Disease Development |
| title_fullStr | Genome-Wide Association and Mechanistic Studies Indicate That Immune Response Contributes to Alzheimer’s Disease Development |
| title_full_unstemmed | Genome-Wide Association and Mechanistic Studies Indicate That Immune Response Contributes to Alzheimer’s Disease Development |
| title_short | Genome-Wide Association and Mechanistic Studies Indicate That Immune Response Contributes to Alzheimer’s Disease Development |
| title_sort | genome wide association and mechanistic studies indicate that immune response contributes to alzheimer s disease development |
| topic | Alzheimer’s disease GWAS SNP mechanism transcription factor binding affinity |
| url | https://www.frontiersin.org/article/10.3389/fgene.2018.00410/full |
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