Methylome-wide association findings for major depressive disorder overlap in blood and brain and replicate in independent brain samples
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We present the first large-scale methylome-wide association studies (MWAS) for major depressive disorder (MDD) to identify sites of potential importance for MDD etiology. Using a sequencing-based approach that provides near-complete coverage of all 28 million common CpGs in the human genome, we assay methylation in MDD cases and controls from both blood (N = 1132) and postmortem brain tissues (N = 61 samples from Brodmann Area 10, BA10). The MWAS for blood identified several loci with P ranging from 1.91 × 10-8 to 4.39 × 10-8 and a resampling approach showed that the cumulative association was significant (P = 4.03 × 10-10) with the signal coming from the top 25,000 MWAS markers. Furthermore, a permutation-based analysis showed significant overlap (P = 5.4 × 10-3) between the MWAS findings in blood and brain (BA10). This overlap was significantly enriched for a number of features including being in eQTLs in blood and the frontal cortex, CpG islands and shores, and exons. The overlapping sites were also enriched for active chromatin states in brain including genic enhancers and active transcription start sites. Furthermore, three loci located in GABBR2, RUFY3, and in an intergenic region on chromosome 2 replicated with the same direction of effect in the second brain tissue (BA25, N = 60) from the same individuals and in two independent brain collections (BA10, N = 81 and 64). GABBR2 inhibits neuronal activity through G protein-coupled second-messenger systems and RUFY3 is implicated in the establishment of neuronal polarity and axon elongation. In conclusion, we identified and replicated methylated loci associated with MDD that are involved in biological functions of likely importance to MDD etiology.
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Three loci located in GABBR2, RUFY3, and an intergenic region on chromosome 2 were replicated in blood and some cortical regions (Brodmann area 10 and 25).
“One study, despite a small sample size, reported that three loci located in GABBR2, RUFY3, and in an intergenic region on chromosome 2, were replicated in blood and some cortical regions (Brodmann area (BA) 10 and 25).82”
From Epigenetic regulation in major depression and other stress-related disorders: molecular mechanisms, clinical relevance and therapeutic potential (2023) · cites this paper as [82]
The Abstract reports that the three named loci replicated in BA25 and two independent BA10 brain collections. The Discussion says they overlapped across blood and brain, but the paper does not report independent replication in blood; that part of the citing sentence overstates the finding. (LLM, conf=0.86)
Experimental — accuracy not yet measuredSome overlap exists between MDD-associated differentially methylated regions in blood and the MDD-associated DMRs in the prefrontal cortex and other brain regions.
“Previous work indicates some overlap between MDD-associated differentially methylated regions (DMRs) in blood and the MDD-associated DMRs in the prefrontal cortex and other brain regions.82–85”
From Epigenetic regulation in major depression and other stress-related disorders: molecular mechanisms, clinical relevance and therapeutic potential (2023) · cites this paper as [82]
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Bruzzone, S. E. P., Ozenne, B., Fisher, P. M., Ortega, G., Jensen, P. S., Dam, V. H., Svarer, C., Knudsen, G. M., Lesch, K., & Frokjaer, V. G. (2024) · Figshare · doi:10.6084/m9.figshare.26726345
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Additional file 3 of DNA methylation of the KLK8 gene in depression symptomatology
Starnawska, A., Bukowski, L., Chernomorchenko, A., Elfving, B., Müller, H. K., van den Oord, E. J. C. G., Åberg, K. A., Guintivano, J., Grove, J., Mors, O., et al. (2021) · Figshare · doi:10.6084/m9.figshare.16907543
Additional file 2 of DNA methylation of the KLK8 gene in depression symptomatology
Starnawska, A., Bukowski, L., Chernomorchenko, A., Elfving, B., Müller, H. K., van den Oord, E. J. C. G., Åberg, K. A., Guintivano, J., Grove, J., Mors, O., et al. (2021) · Figshare · doi:10.6084/m9.figshare.16907540
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- Authors
- Aberg, K. A., Dean, B., Shabalin, A. A., Chan, R. F., Han, L. K. M., Zhao, M., van Grootheest, G., Xie, L. Y., Milaneschi, Y., Clark, S. L., Turecki, G., Penninx, B. W. J. H., & van den Oord, E. J. C. G.
- Affiliations
- Florey Institute of Neuroscience and Mental Health (AU)
- Virginia Commonwealth University (US)
- Amsterdam Neuroscience (NL)
- Douglas Mental Health University Institute (CA)
- ORCID
- Venue
- Molecular Psychiatry
- Published
- 2018-09-21
- Volume
- 25
- Issue
- 6
- Pages
- 1344-1354
- ISSN
- 1359-4184 (ISSN-L)
- 1476-5578
- PMC
- PMC6428621
- OpenAlex
- W2890450469
- Cited by
- 73
- References
- 77
- Citations by year
- 2026: 6 · 2025: 4 · 2024: 11 · 2023: 9 · 2022: 8 · 2021: 13 · 2020: 11 · 2019: 10 · 2018: 1
- FWCI
- 3.11
- Type
- journal article
- Language
- en
- Open access
- green
- pure.amsterdamumc.nl
- Licence
- Locations
- Molecular Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- Pure Amsterdam UMC (publishedVersion, other-oa)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Minerva Access (University of Melbourne) (submittedVersion)
- Amsterdam UMC (VU Amsterdam) - Institutional Repository (submittedVersion)
- Swinburne figshare (Swinburne University of Technology) (submittedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Funders
- U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (R01MH099110)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Keywords
- major depressive disorder, DNA methylation, methylome-wide association study, blood DNA, postmortem brain, Brodmann area 10, frontal cortex, replication, GABBR2, CpG islands, enhancers, transcription start sites, expression quantitative trait loci
- MeSH terms
- Epigenome, Brain, Chromosomes, Human, Pair 2, Cytoskeletal Proteins, Major Depressive Disorder, Depressive Disorder, Major, Female, Humans, Male, Middle Aged, Receptors, GABA-B, CpG Islands, DNA Methylation, DNA, Intergenic, Genome-Wide Association Study
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