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. 2015 Jan;72(1):15-24.
doi: 10.1001/jamaneurol.2014.3049.

Association of Brain DNA methylation in SORL1, ABCA7, HLA-DRB5, SLC24A4, and BIN1 with pathological diagnosis of Alzheimer disease

Lei Yu  1 , Lori B Chibnik  2 , Gyan P Srivastava  2 , Nathalie Pochet  2 , Jingyun Yang  1 , Jishu Xu  2 , James Kozubek  2 , Nikolaus Obholzer  2 , Sue E Leurgans  3 , Julie A Schneider  4 , Alexander Meissner  5 , Philip L De Jager  2 , David A Bennett  1
Affiliations

Association of Brain DNA methylation in SORL1, ABCA7, HLA-DRB5, SLC24A4, and BIN1 with pathological diagnosis of Alzheimer disease

Lei Yu et al. JAMA Neurol. 2015 Jan.

Abstract

Importance: Recent large-scale genome-wide association studies have discovered several genetic variants associated with Alzheimer disease (AD); however, the extent to which DNA methylation in these AD loci contributes to the disease susceptibility remains unknown.

Objective: To examine the association of brain DNA methylation in 28 reported AD loci with AD pathologies.

Design, setting, and participants: Ongoing community-based clinical pathological cohort studies of aging and dementia (the Religious Orders Study and the Rush Memory and Aging Project) among 740 autopsied participants 66.0 to 108.3 years old.

Exposures: DNA methylation levels at individual CpG sites generated from dorsolateral prefrontal cortex tissue using a bead assay.

Main outcomes and measures: Pathological diagnosis of AD by National Institute on Aging-Reagan criteria following a standard postmortem examination.

Results: Overall, 447 participants (60.4%) met the criteria for pathological diagnosis of AD. Brain DNA methylation in SORL1, ABCA7, HLA-DRB5, SLC24A4, and BIN1 was associated with pathological AD. The association was robustly retained after replacing the binary trait of pathological AD with 2 quantitative and molecular specific hallmarks of AD, namely, Aβ load and paired helical filament tau tangle density. Furthermore, RNA expression of transcripts of SORL1 and ABCA7 was associated with paired helical filament tau tangle density, and the expression of BIN1 was associated with Aβ load.

Conclusions and relevance: Brain DNA methylation in multiple AD loci is associated with AD pathologies. The results provide further evidence that disruption of DNA methylation is involved in the pathological process of AD.

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Figures

Figure 1
Figure 1. DNA Methylation With Pathological Alzheimer Disease Diagnosis in Associated Loci
For each locus, the left panel shows the histogram and density function of the global test statistic generated from randomly permuted data, with a blue dashed line superimposed to represent the value of the same statistic observed from the actual data. The right panel is the volcano plot showing the significance level vs the regression estimates for individual CpG sites.
Figure 2
Figure 2. Association Plot for the SORL1 and ABCA7 Loci
A, Association plot for the SORL1 locus. P values of individual CpG sites for each of the 3 Alzheimer disease pathological indexes (red diamond indicates pathological Alzheimer disease; black diamond, Aβ load; and red circle, tau tangle density) were plotted against their genomic positions. The color band on the x-axis represents the chromatic state of the region. The smallest P value for each outcome is highlighted with larger symbols. B, Association plot for the ABCA7 locus. CNV/rep indicates copy number variation/repetitive; PC, Polycomb; and TSS, transcription start site.
Figure 3
Figure 3. Association Plot for the HLA-DRB5 and SLC24A4 Loci
A, Association plot for the HLA-DRB5 locus. P values of individual CpG sites for each of the 3 Alzheimer disease pathological indexes (red diamond indicates pathological Alzheimer disease; black diamond, Aβ load; and red circle, tau tangle density) were plotted against their genomic positions. B, Association plot for the SLC24A4 locus. CNV/rep indicates copy number variation/repetitive; PC, Polycomb; and TSS, transcription start site.
Figure 4
Figure 4. Association Plot for the BIN1 Locus
P values of individual CpG sites for each of the 3 Alzheimer disease pathological indexes (red diamond indicates pathological Alzheimer disease; black diamond, Aβ load; and red circle, tau tangle density) were plotted against their genomic positions. CNV/rep indicates copy number variation/repetitive; PC, Polycomb; and TSS, transcription start site.
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