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Cited by 196Epigenetics and DNA MethylationDementia and Cognitive Impairment ResearchAlzheimer's disease research and treatments

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Elevated DNA methylation across a 48‐kb region spanning the HOXA gene cluster is associated with Alzheimer's disease neuropathology

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Smith, Rebecca G., Hannon, Eilis, De Jager, Philip L., Chibnik, Lori, Lott, Simon J., Condliffe, Daniel, Smith, Adam R., Haroutunian, Vahram, Troakes, Claire, Al‐Sarraj, Safa, Bennett, David A., Powell, John, Lovestone, Simon, Schalkwyk, Leonard, Mill, Jonathan, Lunnon, Katie·2018·Alzheimer's & Dementia
DOI 10.1016/j.jalz.2018.01.017PMC PMC6438205
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Abstract

Introduction: Alzheimer's disease is a neurodegenerative disorder that is hypothesized to involve epigenetic dysregulation of gene expression in the brain. Methods: We performed an epigenome‐wide association study to identify differential DNA methylation associated with neuropathology in prefrontal cortex and superior temporal gyrus samples from 147 individuals, replicating our findings in two independent data sets (N = 117 and 740). Results: We identify elevated DNA methylation associated with neuropathology across a 48‐kb region spanning 208 CpG sites within the HOXA gene cluster. A meta‐analysis of the top‐ranked probe within the HOXA3 gene (cg22962123) highlighted significant hypermethylation across all three cohorts (P = 3.11 × 10−18). Discussion: We present robust evidence for elevated DNA methylation associated with Alzheimer's disease neuropathology spanning the HOXA gene cluster on chromosome 7. These data add to the growing evidence highlighting a role for epigenetic variation in Alzheimer's disease, implicating the HOX gene family as a target for future investigation.

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Fig. 1. HOXA3 hypermethylation is associated with neuropathological measures of AD in cortex. (A) A Manhattan plot of association between DNA methylation in the PFC with Braak stage highlights associations at loci across the genome, with a region on chromosome 7 in the HOXA3 gene showing the greatest number of probes associated with pathology. The red line indicates experiment-wide significance threshold (P = 2.2 × 10−7), with the green line indicating a more relaxed significance threshold (P = 1 × 10−5). (B) Using a sliding window approach to identify differentially methylated regions, we identified six within the HOXA gene cluster (Table 2), with the most significant region spanning 364 bp in the HOXA3 gene and containing seven CpG sites that showed increased methylation in late-stage AD (Braak stage VI) compared to healthy controls (Braak stage 0). (C) A mini-Manhattan plot across the HOXA gene cluster. Highlighted between gray dashed lines is a 48,754-bp region containing 208 probes characterized by neuropathology-associated hypermethylation. Red circles indicate increased DNA methylation in disease (≥1% between Braak 0 and Braak VI), green circles indicate decreased DNA methylation in disease (≥1% between Braak 0 and Braak VI), and black circles indicate DNA methylation differences <1% between Braak 0 and Braak VI. (D) The site demonstrating the greatest DNA methylation difference (cg22962123) in the PFC (R = 0.36, P = 1.2 × 10−7) also showed a similar but weaker association in the STG (R = 0.28, P = 2.78 × 10−4). (E) A quadrant plot of the effect size of the 208 probes identified in the PFC and their corresponding effect size in the STG highlights a significant correlation between brain regions (R = 0.76, P = 2.66 × 10−40). Abbreviations: AD, Alzheimer’s disease; CpG, 5′-C-phosphate-G-3′; PFC, prefrontal cortex; STG, superior temporal gyrus.
Fig. 1. HOXA3 hypermethylation is associated with neuropathological measures of AD in cortex. (A) A Manhattan plot of association between DNA methylation in the PFC with Braak stage highlights associations at loci across the genome, with a region on chromosome 7 in the HOXA3 gene showing the greatest number of probes associated with pathology. The red line indicates experiment-wide significance threshold (P = 2.2 × 10−7), with the green line indicating a more relaxed significance threshold (P = 1 × 10−5). (B) Using a sliding window approach to identify differentially methylated regions, we identified six within the HOXA gene cluster (Table 2), with the most significant region spanning 364 bp in the HOXA3 gene and containing seven CpG sites that showed increased methylation in late-stage AD (Braak stage VI) compared to healthy controls (Braak stage 0). (C) A mini-Manhattan plot across the HOXA gene cluster. Highlighted between gray dashed lines is a 48,754-bp region containing 208 probes characterized by neuropathology-associated hypermethylation. Red circles indicate increased DNA methylation in disease (≥1% between Braak 0 and Braak VI), green circles indicate decreased DNA methylation in disease (≥1% between Braak 0 and Braak VI), and black circles indicate DNA methylation differences <1% between Braak 0 and Braak VI. (D) The site demonstrating the greatest DNA methylation difference (cg22962123) in the PFC (R = 0.36, P = 1.2 × 10−7) also showed a similar but weaker association in the STG (R = 0.28, P = 2.78 × 10−4). (E) A quadrant plot of the effect size of the 208 probes identified in the PFC and their corresponding effect size in the STG highlights a significant correlation between brain regions (R = 0.76, P = 2.66 × 10−40). Abbreviations: AD, Alzheimer’s disease; CpG, 5′-C-phosphate-G-3′; PFC, prefrontal cortex; STG, superior temporal gyrus.CC BY-NC-ND · PubMed Central
Fig. 2. Replication of neuropathology-associated DNA methylation differences across the HOXA gene cluster in additional study cohorts. (A) We identified a consistent pattern of increased DNA methylation across the HOXA cluster in the London (Lunnon et al.) cohort in the PFC (B) with a strong correlation in effect size across the 208 probes in the region between data sets (R = 0.74, P = 2.24 × 10−37). (C) A similar pattern of DNA methylation changes was observed in the PFC in the ROS/MAP (De Jager et al.) cohort, (D) with a strong correlation in effect size across the 208 probes in the region between data sets (R = 0.80, P = 2.39 × 10−48). (E) A Fisher’s combined P value meta-analysis of the PFC with respect to Braak stage across all three cohorts showed striking patterns of increased DNA methylation with many probes in the HOXA3 region reaching experiment-wide significance. (F) The most significant probe identified from the discovery cohort (cg22962123) was also the most significant probe in the meta-analysis (P = 3.11 × 10−18) and characterized by neuropathology-associated hypermethylation across all three cohorts. In plots (A) and (C) red circles indicate increased DNA methylation in disease (≥1% between Braak 0 and Braak VI), green circles indicate decreased DNA methylation in disease (≥1% between Braak 0 and Braak VI), and black circles indicate DNA methylation differences <1% between Braak 0 and Braak VI. In plots (A), (C), and (E), the red line indicates experiment-wide significance (P = 2.2 × 10−7), whereas the blue line indicates significance after correcting for 208 tests (P = 2.4 × 10−4). In plots (A), (C), and (E), the gray dashed lines indicate the same region across the graphs for reference. These show the probes in the extended DMR. In plot (F), red denotes the PFC and green denotes the STG. Abbreviations: DMR, differentially methylated region; PFC, prefrontal cortex; ROS/MAP, Religious Orders Study/Memory and Aging Project; STG, superior temporal gyrus.
Fig. 2. Replication of neuropathology-associated DNA methylation differences across the HOXA gene cluster in additional study cohorts. (A) We identified a consistent pattern of increased DNA methylation across the HOXA cluster in the London (Lunnon et al.) cohort in the PFC (B) with a strong correlation in effect size across the 208 probes in the region between data sets (R = 0.74, P = 2.24 × 10−37). (C) A similar pattern of DNA methylation changes was observed in the PFC in the ROS/MAP (De Jager et al.) cohort, (D) with a strong correlation in effect size across the 208 probes in the region between data sets (R = 0.80, P = 2.39 × 10−48). (E) A Fisher’s combined P value meta-analysis of the PFC with respect to Braak stage across all three cohorts showed striking patterns of increased DNA methylation with many probes in the HOXA3 region reaching experiment-wide significance. (F) The most significant probe identified from the discovery cohort (cg22962123) was also the most significant probe in the meta-analysis (P = 3.11 × 10−18) and characterized by neuropathology-associated hypermethylation across all three cohorts. In plots (A) and (C) red circles indicate increased DNA methylation in disease (≥1% between Braak 0 and Braak VI), green circles indicate decreased DNA methylation in disease (≥1% between Braak 0 and Braak VI), and black circles indicate DNA methylation differences <1% between Braak 0 and Braak VI. In plots (A), (C), and (E), the red line indicates experiment-wide significance (P = 2.2 × 10−7), whereas the blue line indicates significance after correcting for 208 tests (P = 2.4 × 10−4). In plots (A), (C), and (E), the gray dashed lines indicate the same region across the graphs for reference. These show the probes in the extended DMR. In plot (F), red denotes the PFC and green denotes the STG. Abbreviations: DMR, differentially methylated region; PFC, prefrontal cortex; ROS/MAP, Religious Orders Study/Memory and Aging Project; STG, superior temporal gyrus.CC BY-NC-ND · PubMed Central

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Authors
Smith, R. G., Hannon, E., De Jager, P. L., Chibnik, L., Lott, S. J., Condliffe, D., Smith, A. R., Haroutunian, V., Troakes, C., Al‐Sarraj, S., Bennett, D. A., Powell, J., Lovestone, S., Schalkwyk, L., Mill, J., & Lunnon, K.
Affiliations
  • University of Exeter (GB)
  • Program in Translational NeuroPsychiatric Genomics Departments of Neurology and Psychiatry Institute for the Neurosciences Brigham and Women's Hospital Boston MA USA
  • Brigham and Women's Hospital (US)
  • King's College London (GB)
  • Queen Mary University of London (GB)
  • James J. Peters VA Medical Center (US)
  • Rush University Medical Center (US)
  • Warneford Hospital (GB)
  • University of Essex (GB)
Corresponding author
  • Mill, Jonathan
  • Lunnon, Katie
ORCID
Venue
Alzheimer's & Dementia
Publisher
Wiley
Published
2018-03-14
Volume
14
Issue
12
Pages
1580-1588
ISSN
  • 1552-5260 (ISSN-L)
  • 1552-5279
DOI
10.1016/j.jalz.2018.01.017
PMC
PMC6438205
OpenAlex
W2789414284
Cited by
184
References
26
Citations by year
2026: 13 · 2025: 20 · 2024: 22 · 2023: 28 · 2022: 26 · 2021: 27 · 2020: 26 · 2019: 15 · 2018: 7
FWCI
7.56
Type
journal article
Language
en
Open access
Licence
Locations
  • Alzheimer s & Dementia (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion, cc-by-nc-nd)
  • Open Access at Essex (University of Essex) (acceptedVersion)
  • Figshare (submittedVersion, cc-by-nc-nd)
  • Research Portal (King's College London) (submittedVersion, other-oa)
  • Open Research Exeter (University of Exeter) (submittedVersion, cc-by-nc-nd)
  • Royal Devon and Exeter Research Repository (Royal Devon and Exeter) (submittedVersion)
Funders
  • National Institutes of Health (R01 AG036039, AG02219, AG05138, MH064673, R01 AG036042, R01AG036836, R01 AG17917, R01 AG15819, R01 AG032990, R01 AG18023, RC2 AG036547, P30 AG10161, P50 AG016574, U01 ES017155, KL2 RR024151, K25 AG041906‐01)
  • Alzheimer's Society (AS‐PG‐14‐038)
  • Alzheimer's Association (NIRG‐14‐320878)
  • BRACE
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
Keywords
Alzheimer's disease, DNA methylation
MeSH terms
Alzheimer Disease, Multigene Family, Temporal Lobe, Prefrontal Cortex, Homeodomain Proteins, CpG Islands, DNA Methylation, Genetic Predisposition to Disease, Epigenesis, Genetic, Genome-Wide Association Study

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