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. 2020 Dec 9;12(1):189.
doi: 10.1186/s13148-020-00984-5.

Longitudinal data in peripheral blood confirm that PM20D1 is a quantitative trait locus (QTL) for Alzheimer's disease and implicate its dynamic role in disease progression

Qi Wang  1 , Yinghua Chen  2 , Benjamin Readhead  3 , Kewei Chen  2 , Yi Su  2 , Eric M Reiman  3   2 , Joel T Dudley  3   4
Affiliations

Longitudinal data in peripheral blood confirm that PM20D1 is a quantitative trait locus (QTL) for Alzheimer's disease and implicate its dynamic role in disease progression

Qi Wang et al. Clin Epigenetics. .

Abstract

Background: While Alzheimer's disease (AD) remains one of the most challenging diseases to tackle, genome-wide genetic/epigenetic studies reveal many disease-associated risk loci, which sheds new light onto disease heritability, provides novel insights to understand its underlying mechanism and potentially offers easily measurable biomarkers for early diagnosis and intervention.

Methods: We analyzed whole-genome DNA methylation data collected from peripheral blood in a cohort (n = 649) from the Alzheimer's Disease Neuroimaging Initiative (ADNI) and compared the DNA methylation level at baseline among participants diagnosed with AD (n = 87), mild cognitive impairment (MCI, n = 175) and normal controls (n = 162), to identify differentially methylated regions (DMRs). We also leveraged up to 4 years of longitudinal DNA methylation data, sampled at approximately 1 year intervals to model alterations in methylation levels at DMRs to delineate methylation changes associated with aging and disease progression, by linear mixed-effects (LME) modeling for the unchanged diagnosis groups (AD, MCI and control, respectively) and U-shape testing for those with changed diagnosis (converters).

Results: When compared with controls, patients with MCI consistently displayed promoter hypomethylation at methylation QTL (mQTL) gene locus PM20D1. This promoter hypomethylation was even more prominent in patients with mild to moderate AD. This is in stark contrast with previously reported hypermethylation in hippocampal and frontal cortex brain tissues in patients with advanced-stage AD at this locus. From longitudinal data, we show that initial promoter hypomethylation of PM20D1 during MCI and early stage AD is reversed to eventual promoter hypermethylation in late stage AD, which helps to complete a fuller picture of methylation dynamics. We also confirm this observation in an independent cohort from the Religious Orders Study and Memory and Aging Project (ROSMAP) Study using DNA methylation and gene expression data from brain tissues as neuropathological staging (Braak score) advances.

Conclusions: Our results confirm that PM20D1 is an mQTL in AD and demonstrate that it plays a dynamic role at different stages of the disease. Further in-depth study is thus warranted to fully decipher its role in the evolution of AD and potentially explore its utility as a blood-based biomarker for AD.

Keywords: Alzheimer’s disease; Epigenetics; Mixed-effects model; PM20D1.

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Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Comparison of individual cell type across control (n = 162), MCI (n = 175) and AD (n = 87) groups with stable diagnosis at baseline measurements. Shown in a granulocytes (Gran), in b CD4T cells, in c CD8T cells, in d natural killer (NK) cells, in e monocytes (Mono) and in f B cells. Blue line indicates comparison between AD cases versus control subjects; black line indicates comparison between MCI cases versus control subjects. P Value for the differences in cell composition estimates across groups as per T test is indicated
Fig. 2
Fig. 2
Graphical representation of differentially methylated region (DMR) near PM20D1 gene locus. Genomic location is indicated by chromosome position based on Genome Reference Consortium Human Build 37 (GRCh37). Transcripts are indicated by light blue arrows. Solid line represents β values for all the CpGs constituting the significant region, where AD is colored in red, MCI in blue and control in green
Fig. 3
Fig. 3
Methylation change as allelic dose of rs708727 changes modeled by β values at baseline regressed with allelic dose of rs708727 at one of the representative CpG probes (cg14159672). Scatter plot is colored by the allelic doses of rs708727 where red = 0 (GG), green = 1 (GA), and blue = 2 (AA). An overall linear fit line is also shown. Panel a depicts control group, b depicts MCI group, and c depicts AD group
Fig. 4
Fig. 4
Methylation change as disease/age progresses modeled by β values regressed with age at one of the representative CpG probes (cg14893161). Scatter plot is colored by the allelic doses of rs708727 where red = 0 (GG), green = 1 (GA), and blue = 2 (AA) in panels a–c. An overall linear fit line is also shown. Panel a depicts control group, b depicts MCI group, and c depicts AD group. Panel d depicts all the conversion cases where a U-shape is fit and a break point is marked
Fig. 5
Fig. 5
Correlation of methylation β values at one of the representative CpG probes (cg05841700) with gene expression of PM20D1 for the ADNI cohort. An overall fit line and the fit lines stratified by the allelic doses of rs708727 are shown
Fig. 6
Fig. 6
Methylation change as disease progresses modeled by β values regressed with Braak score at one of the representative CpG probes (cg26354017) from the ROSMAP brain samples. Scatter plot is colored by the allelic doses of rs708727 where red = 0 (GG), green = 1 (GA), and blue = 2 (AA). An overall linear fit line is also shown. Panel a depicts control group, b depicts MCI group, and c depicts AD group
Fig. 7
Fig. 7
Workflow and subject selection for the study outlined in this work
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