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BMC Med Genomics. 2017 May 24;10(Suppl 1):29. doi: 10.1186/s12920-017-0267-0.

Association analysis of rare variants near the APOE region with CSF and neuroimaging biomarkers of Alzheimer's disease.

Author information

1
Center for Neuroimaging, Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, IN, USA. knho@iupui.edu.
2
Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, IN, USA. knho@iupui.edu.
3
Indiana Alzheimer's Disease Center, Indiana University School of Medicine, Indianapolis, IN, USA. knho@iupui.edu.
4
Center for Neuroimaging, Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, IN, USA.
5
Department of Electrical and Computer Engineering, State University of New York at Oswego, Oswego, NY, USA.
6
Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA.
7
Indiana Alzheimer's Disease Center, Indiana University School of Medicine, Indianapolis, IN, USA.
8
Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, IN, USA.
9
Department of Biomedical and Translational Informatics, Geisinger Health System, Danville, PA, USA.
10
Department of Biostatistics, School of Public Health, University of Michigan, Ann Arbor, MI, USA.
11
Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA, USA.
12
Department of Neuroscience, University of California-San Diego, San Diego, CA, USA.
13
Department of Neurology, Mayo Clinic Minnesota, Rochester, MN, USA.
14
Department of Radiology, Mayo Clinic Minnesota, Rochester, MN, USA.
15
Departments of Radiology, Medicine, and Psychiatry, University of California-San Francisco, San Francisco, CA, USA.
16
Department of Veterans Affairs Medical Center, San Francisco, CA, USA.
17
Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
18
The Institute for Neuroimaging and Informatics and Laboratory of Neuro Imaging, Keck School of Medicine of USC, University of Southern California, Los Angeles, CA, USA.
19
Center for Neuroimaging, Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, IN, USA. asaykin@iu.edu.
20
Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA. asaykin@iu.edu.
21
Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, IN, USA. asaykin@iu.edu.
22
Indiana Alzheimer's Disease Center, Indiana University School of Medicine, Indianapolis, IN, USA. asaykin@iu.edu.

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.

KEYWORDS:

ADNI; CSF; Near APOE; Neuroimaging; Rare variants; Whole genome sequencing

PMID:
28589856
PMCID:
PMC5461522
DOI:
10.1186/s12920-017-0267-0
[Indexed for MEDLINE]
Free PMC Article

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