Genome-Wide Association Analysis across Endophenotypes in Alzheimer’s Disease: Main Effects and Disease Stage-Specific Interactions
The underlying genetic susceptibility for Alzheimer’s disease (AD) is not yet fully understood. The heterogeneous nature of the disease challenges genetic association studies. Endophenotype approaches can help to address this challenge by more direct interrogation of biological traits related to the...
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MDPI AG
2023-10-01
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| Series: | Genes |
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| Online Access: | https://www.mdpi.com/2073-4425/14/11/2010 |
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| author | Thea J. Rosewood Kwangsik Nho Shannon L. Risacher Sujuan Gao Li Shen Tatiana Foroud Andrew J. Saykin on behalf of the Alzheimer’s Disease Neuroimaging Initiative |
| author_facet | Thea J. Rosewood Kwangsik Nho Shannon L. Risacher Sujuan Gao Li Shen Tatiana Foroud Andrew J. Saykin on behalf of the Alzheimer’s Disease Neuroimaging Initiative |
| author_sort | Thea J. Rosewood |
| collection | DOAJ |
| description | The underlying genetic susceptibility for Alzheimer’s disease (AD) is not yet fully understood. The heterogeneous nature of the disease challenges genetic association studies. Endophenotype approaches can help to address this challenge by more direct interrogation of biological traits related to the disease. AD endophenotypes based on amyloid-β, tau, and neurodegeneration (A/T/N) biomarkers and cognitive performance were selected from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort (N = 1565). A genome-wide association study (GWAS) of quantitative phenotypes was performed using an SNP main effect and an SNP by Diagnosis interaction (SNP × DX) model to identify disease stage-specific genetic effects. Nine loci were identified as study-wide significant with one or more A/T/N endophenotypes in the main effect model, as well as additional findings significantly associated with cognitive measures. These nine loci include SNPs in or near the genes APOE, SRSF10, HLA-DQB1, XKR3, and KIAA1671. The SNP × DX model identified three study-wide significant genetic loci (BACH2, EP300, and PACRG-AS1) with a neuroprotective effect in later AD stage endophenotypes. An endophenotype approach identified novel genetic associations and provided insight into the molecular mechanisms underlying the genetic associations that may otherwise be missed using conventional case-control study designs. |
| first_indexed | 2024-03-09T16:47:41Z |
| format | Article |
| id | doaj.art-32ade5ba42bc48da9adf61b52abfc74e |
| institution | Directory Open Access Journal |
| issn | 2073-4425 |
| language | English |
| last_indexed | 2024-03-09T16:47:41Z |
| publishDate | 2023-10-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Genes |
| spelling | doaj.art-32ade5ba42bc48da9adf61b52abfc74e2023-11-24T14:43:42ZengMDPI AGGenes2073-44252023-10-011411201010.3390/genes14112010Genome-Wide Association Analysis across Endophenotypes in Alzheimer’s Disease: Main Effects and Disease Stage-Specific InteractionsThea J. Rosewood0Kwangsik Nho1Shannon L. Risacher2Sujuan Gao3Li Shen4Tatiana Foroud5Andrew J. Saykin6on behalf of the Alzheimer’s Disease Neuroimaging InitiativeIndiana Alzheimer’s Disease Research Center, Indianapolis, IN 46202, USAIndiana Alzheimer’s Disease Research Center, Indianapolis, IN 46202, USAIndiana Alzheimer’s Disease Research Center, Indianapolis, IN 46202, USAIndiana Alzheimer’s Disease Research Center, Indianapolis, IN 46202, USADepartment of Biostatistics, Epidemiology and Informatics, The Perelman School of Medicine, Philadelphia, PA 19104, USAIndiana Alzheimer’s Disease Research Center, Indianapolis, IN 46202, USAIndiana Alzheimer’s Disease Research Center, Indianapolis, IN 46202, USAThe underlying genetic susceptibility for Alzheimer’s disease (AD) is not yet fully understood. The heterogeneous nature of the disease challenges genetic association studies. Endophenotype approaches can help to address this challenge by more direct interrogation of biological traits related to the disease. AD endophenotypes based on amyloid-β, tau, and neurodegeneration (A/T/N) biomarkers and cognitive performance were selected from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort (N = 1565). A genome-wide association study (GWAS) of quantitative phenotypes was performed using an SNP main effect and an SNP by Diagnosis interaction (SNP × DX) model to identify disease stage-specific genetic effects. Nine loci were identified as study-wide significant with one or more A/T/N endophenotypes in the main effect model, as well as additional findings significantly associated with cognitive measures. These nine loci include SNPs in or near the genes APOE, SRSF10, HLA-DQB1, XKR3, and KIAA1671. The SNP × DX model identified three study-wide significant genetic loci (BACH2, EP300, and PACRG-AS1) with a neuroprotective effect in later AD stage endophenotypes. An endophenotype approach identified novel genetic associations and provided insight into the molecular mechanisms underlying the genetic associations that may otherwise be missed using conventional case-control study designs.https://www.mdpi.com/2073-4425/14/11/2010geneticsGWASendophenotypeAPOEgenetic interactioncerebrospinal fluid biomarkers |
| spellingShingle | Thea J. Rosewood Kwangsik Nho Shannon L. Risacher Sujuan Gao Li Shen Tatiana Foroud Andrew J. Saykin on behalf of the Alzheimer’s Disease Neuroimaging Initiative Genome-Wide Association Analysis across Endophenotypes in Alzheimer’s Disease: Main Effects and Disease Stage-Specific Interactions Genes genetics GWAS endophenotype APOE genetic interaction cerebrospinal fluid biomarkers |
| title | Genome-Wide Association Analysis across Endophenotypes in Alzheimer’s Disease: Main Effects and Disease Stage-Specific Interactions |
| title_full | Genome-Wide Association Analysis across Endophenotypes in Alzheimer’s Disease: Main Effects and Disease Stage-Specific Interactions |
| title_fullStr | Genome-Wide Association Analysis across Endophenotypes in Alzheimer’s Disease: Main Effects and Disease Stage-Specific Interactions |
| title_full_unstemmed | Genome-Wide Association Analysis across Endophenotypes in Alzheimer’s Disease: Main Effects and Disease Stage-Specific Interactions |
| title_short | Genome-Wide Association Analysis across Endophenotypes in Alzheimer’s Disease: Main Effects and Disease Stage-Specific Interactions |
| title_sort | genome wide association analysis across endophenotypes in alzheimer s disease main effects and disease stage specific interactions |
| topic | genetics GWAS endophenotype APOE genetic interaction cerebrospinal fluid biomarkers |
| url | https://www.mdpi.com/2073-4425/14/11/2010 |
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