Association analysis of rare variants near the APOE region with CSF and neuroimaging biomarkers of Alzheimer’s disease
Abstract Background The APOE ε4 allele is the most significant common genetic risk factor for late-onset Alzheimer’s disease (LOAD). The region surrounding APOE on chromosome 19 has also shown consistent association with LOAD. However, no common variants in the region remain significant after adjust...
| Main Authors: | , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2017-05-01
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| Series: | BMC Medical Genomics |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s12920-017-0267-0 |
| _version_ | 1819122785556889600 |
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| author | Kwangsik Nho Sungeun Kim Emrin Horgusluoglu Shannon L. Risacher Li Shen Dokyoon Kim Seunggeun Lee Tatiana Foroud Leslie M. Shaw John Q. Trojanowski Paul S. Aisen Ronald C. Petersen Clifford R. Jack Michael W. Weiner Robert C. Green Arthur W. Toga Andrew J. Saykin for the Alzheimer’s Disease Neuroimaging Initiative (ADNI) |
| author_facet | Kwangsik Nho Sungeun Kim Emrin Horgusluoglu Shannon L. Risacher Li Shen Dokyoon Kim Seunggeun Lee Tatiana Foroud Leslie M. Shaw John Q. Trojanowski Paul S. Aisen Ronald C. Petersen Clifford R. Jack Michael W. Weiner Robert C. Green Arthur W. Toga Andrew J. Saykin for the Alzheimer’s Disease Neuroimaging Initiative (ADNI) |
| author_sort | Kwangsik Nho |
| collection | DOAJ |
| description | Abstract Background The APOE ε4 allele is the most significant common genetic risk factor for late-onset Alzheimer’s disease (LOAD). The region surrounding APOE on chromosome 19 has also shown consistent association with LOAD. However, no common variants in the region remain significant after adjusting for APOE genotype. We report a rare variant association analysis of genes in the vicinity of APOE with cerebrospinal fluid (CSF) and neuroimaging biomarkers of LOAD. Methods Whole genome sequencing (WGS) was performed on 817 blood DNA samples from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Sequence data from 757 non-Hispanic Caucasian participants was used in the present analysis. We extracted all rare variants (MAF (minor allele frequency) < 0.05) within a 312 kb window in APOE’s vicinity encompassing 12 genes. We assessed CSF and neuroimaging (MRI and PET) biomarkers as LOAD-related quantitative endophenotypes. Gene-based analyses of rare variants were performed using the optimal Sequence Kernel Association Test (SKAT-O). Results A total of 3,334 rare variants (MAF < 0.05) were found within the APOE region. Among them, 72 rare non-synonymous variants were observed. Eight genes spanning the APOE region were significantly associated with CSF Aβ1-42 (p < 1.0 × 10−3). After controlling for APOE genotype and adjusting for multiple comparisons, 4 genes (CBLC, BCAM, APOE, and RELB) remained significant. Whole-brain surface-based analysis identified highly significant clusters associated with rare variants of CBLC in the temporal lobe region including the entorhinal cortex, as well as frontal lobe regions. Whole-brain voxel-wise analysis of amyloid PET identified significant clusters in the bilateral frontal and parietal lobes showing associations of rare variants of RELB with cortical amyloid burden. Conclusions Rare variants within genes spanning the APOE region are significantly associated with LOAD-related CSF Aβ1-42 and neuroimaging biomarkers after adjusting for APOE genotype. These findings warrant further investigation and illustrate the role of next generation sequencing and quantitative endophenotypes in assessing rare variants which may help explain missing heritability in AD and other complex diseases. |
| first_indexed | 2024-12-22T06:57:58Z |
| format | Article |
| id | doaj.art-76a4ec0965754d1681c63c08b1ea7026 |
| institution | Directory Open Access Journal |
| issn | 1755-8794 |
| language | English |
| last_indexed | 2024-12-22T06:57:58Z |
| publishDate | 2017-05-01 |
| publisher | BMC |
| record_format | Article |
| series | BMC Medical Genomics |
| spelling | doaj.art-76a4ec0965754d1681c63c08b1ea70262022-12-21T18:34:53ZengBMCBMC Medical Genomics1755-87942017-05-0110S1455210.1186/s12920-017-0267-0Association analysis of rare variants near the APOE region with CSF and neuroimaging biomarkers of Alzheimer’s diseaseKwangsik Nho0Sungeun Kim1Emrin Horgusluoglu2Shannon L. Risacher3Li Shen4Dokyoon Kim5Seunggeun Lee6Tatiana Foroud7Leslie M. Shaw8John Q. Trojanowski9Paul S. Aisen10Ronald C. Petersen11Clifford R. Jack12Michael W. Weiner13Robert C. Green14Arthur W. Toga15Andrew J. Saykin16for the Alzheimer’s Disease Neuroimaging Initiative (ADNI)Center for Neuroimaging, Department of Radiology and Imaging Sciences, Indiana University School of MedicineCenter for Neuroimaging, Department of Radiology and Imaging Sciences, Indiana University School of MedicineDepartment of Medical and Molecular Genetics, Indiana University School of MedicineCenter for Neuroimaging, Department of Radiology and Imaging Sciences, Indiana University School of MedicineCenter for Neuroimaging, Department of Radiology and Imaging Sciences, Indiana University School of MedicineDepartment of Biomedical and Translational Informatics, Geisinger Health SystemDepartment of Biostatistics, School of Public Health, University of MichiganCenter for Neuroimaging, Department of Radiology and Imaging Sciences, Indiana University School of MedicineDepartment of Pathology and Laboratory Medicine, University of Pennsylvania School of MedicineDepartment of Pathology and Laboratory Medicine, University of Pennsylvania School of MedicineDepartment of Neuroscience, University of California-San DiegoDepartment of Neurology, Mayo Clinic MinnesotaDepartment of Radiology, Mayo Clinic MinnesotaDepartments of Radiology, Medicine, and Psychiatry, University of California-San FranciscoDivision of Genetics, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical SchoolThe Institute for Neuroimaging and Informatics and Laboratory of Neuro Imaging, Keck School of Medicine of USC, University of Southern CaliforniaCenter for Neuroimaging, Department of Radiology and Imaging Sciences, Indiana University School of MedicineAbstract Background The APOE ε4 allele is the most significant common genetic risk factor for late-onset Alzheimer’s disease (LOAD). The region surrounding APOE on chromosome 19 has also shown consistent association with LOAD. However, no common variants in the region remain significant after adjusting for APOE genotype. We report a rare variant association analysis of genes in the vicinity of APOE with cerebrospinal fluid (CSF) and neuroimaging biomarkers of LOAD. Methods Whole genome sequencing (WGS) was performed on 817 blood DNA samples from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Sequence data from 757 non-Hispanic Caucasian participants was used in the present analysis. We extracted all rare variants (MAF (minor allele frequency) < 0.05) within a 312 kb window in APOE’s vicinity encompassing 12 genes. We assessed CSF and neuroimaging (MRI and PET) biomarkers as LOAD-related quantitative endophenotypes. Gene-based analyses of rare variants were performed using the optimal Sequence Kernel Association Test (SKAT-O). Results A total of 3,334 rare variants (MAF < 0.05) were found within the APOE region. Among them, 72 rare non-synonymous variants were observed. Eight genes spanning the APOE region were significantly associated with CSF Aβ1-42 (p < 1.0 × 10−3). After controlling for APOE genotype and adjusting for multiple comparisons, 4 genes (CBLC, BCAM, APOE, and RELB) remained significant. Whole-brain surface-based analysis identified highly significant clusters associated with rare variants of CBLC in the temporal lobe region including the entorhinal cortex, as well as frontal lobe regions. Whole-brain voxel-wise analysis of amyloid PET identified significant clusters in the bilateral frontal and parietal lobes showing associations of rare variants of RELB with cortical amyloid burden. Conclusions Rare variants within genes spanning the APOE region are significantly associated with LOAD-related CSF Aβ1-42 and neuroimaging biomarkers after adjusting for APOE genotype. These findings warrant further investigation and illustrate the role of next generation sequencing and quantitative endophenotypes in assessing rare variants which may help explain missing heritability in AD and other complex diseases.http://link.springer.com/article/10.1186/s12920-017-0267-0Whole genome sequencingRare variantsNear APOEADNICSFNeuroimaging |
| spellingShingle | Kwangsik Nho Sungeun Kim Emrin Horgusluoglu Shannon L. Risacher Li Shen Dokyoon Kim Seunggeun Lee Tatiana Foroud Leslie M. Shaw John Q. Trojanowski Paul S. Aisen Ronald C. Petersen Clifford R. Jack Michael W. Weiner Robert C. Green Arthur W. Toga Andrew J. Saykin for the Alzheimer’s Disease Neuroimaging Initiative (ADNI) Association analysis of rare variants near the APOE region with CSF and neuroimaging biomarkers of Alzheimer’s disease BMC Medical Genomics Whole genome sequencing Rare variants Near APOE ADNI CSF Neuroimaging |
| title | Association analysis of rare variants near the APOE region with CSF and neuroimaging biomarkers of Alzheimer’s disease |
| title_full | Association analysis of rare variants near the APOE region with CSF and neuroimaging biomarkers of Alzheimer’s disease |
| title_fullStr | Association analysis of rare variants near the APOE region with CSF and neuroimaging biomarkers of Alzheimer’s disease |
| title_full_unstemmed | Association analysis of rare variants near the APOE region with CSF and neuroimaging biomarkers of Alzheimer’s disease |
| title_short | Association analysis of rare variants near the APOE region with CSF and neuroimaging biomarkers of Alzheimer’s disease |
| title_sort | association analysis of rare variants near the apoe region with csf and neuroimaging biomarkers of alzheimer s disease |
| topic | Whole genome sequencing Rare variants Near APOE ADNI CSF Neuroimaging |
| url | http://link.springer.com/article/10.1186/s12920-017-0267-0 |
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