Genome-wide DNA methylation meta-analysis in the brains of suicide completers.
Journal
Translational psychiatry
ISSN: 2158-3188
Titre abrégé: Transl Psychiatry
Pays: United States
ID NLM: 101562664
Informations de publication
Date de publication:
19 02 2020
19 02 2020
Historique:
received:
18
12
2019
accepted:
30
01
2020
revised:
09
01
2020
entrez:
21
2
2020
pubmed:
23
2
2020
medline:
22
6
2021
Statut:
epublish
Résumé
Suicide is the second leading cause of death globally among young people representing a significant global health burden. Although the molecular correlates of suicide remains poorly understood, it has been hypothesised that epigenomic processes may play a role. The objective of this study was to identify suicide-associated DNA methylation changes in the human brain by utilising previously published and unpublished methylomic datasets. We analysed prefrontal cortex (PFC, n = 211) and cerebellum (CER, n = 114) DNA methylation profiles from suicide completers and non-psychiatric, sudden-death controls, meta-analysing data from independent cohorts for each brain region separately. We report evidence for altered DNA methylation at several genetic loci in suicide cases compared to controls in both brain regions with suicide-associated differentially methylated positions enriched among functional pathways relevant to psychiatric phenotypes and suicidality, including nervous system development (PFC) and regulation of long-term synaptic depression (CER). In addition, we examined the functional consequences of variable DNA methylation within a PFC suicide-associated differentially methylated region (PSORS1C3 DMR) using a dual luciferase assay and examined expression of nearby genes. DNA methylation within this region was associated with decreased expression of firefly luciferase but was not associated with expression of nearby genes, PSORS1C3 and POU5F1. Our data suggest that suicide is associated with DNA methylation, offering novel insights into the molecular pathology associated with suicidality.
Identifiants
pubmed: 32075955
doi: 10.1038/s41398-020-0752-7
pii: 10.1038/s41398-020-0752-7
pmc: PMC7031296
doi:
Substances chimiques
PSORS1C3 lncRNA, human
0
Proteins
0
RNA, Long Noncoding
0
Types de publication
Journal Article
Meta-Analysis
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
69Subventions
Organisme : Fonds de Recherche du Québec-Société et Culture (FRQSC)
ID : NA
Pays : International
Organisme : Medical Research Council
ID : MR/K013807/1
Pays : United Kingdom
Organisme : Fondation Brain Canada (Fondation Neuro Canada)
ID : NA
Pays : International
Organisme : NIMH NIH HHS
ID : R21 MH094771
Pays : United States
Organisme : Brain and Behavior Research Foundation (Brain & Behavior Research Foundation)
ID : MR/K013807/1
Pays : International
Organisme : RCUK | MRC | Medical Research Foundation
ID : MR/K013807/1
Pays : International
Organisme : U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (NIMH)
ID : NIMH 1R21MH094771
Pays : International
Références
CDC. Suicide Mortality by State Report. https://www.cdc.gov/nchs/pressroom/sosmap/suicide-mortality/suicide.htm (2017).
WHO. Global Health Observatory (GHO) Data. https://www.who.int/news-room/fact-sheets/detail/suicide (2018)
Malone, K. M. et al. Protective factors against suicidal acts in major depression: reasons for living. Am. J. Psychiatry 157, 1084–1088 (2000).
pubmed: 10873915
Schosser, A. et al. Genomewide association scan of suicidal thoughts and behaviour in major depression. PLoS ONE 6, e20690 (2011).
pubmed: 21750702
pmcid: 3130038
Willour, V. L. et al. A genome-wide association study of attempted suicide. Mol. Psychiatry 17, 433–444 (2012).
pubmed: 21423239
Galfalvy, H. et al. A pilot genome wide association and gene expression array study of suicide with and without major depression. World J. Biol. Psychiatry 14, 574–582 (2013).
pubmed: 22059935
Mullins, N. et al. GWAS of suicide attempt in psychiatric disorders and association with major depression polygenic risk scores. Am. J. Psychiatry. https://doi.org/10.1176/appiajp201918080957 (2019).
Policicchio, S., Dempster, E. L. & Murphy, T. M. Deciphering the epigenetic landscape of suicidal behaviour: a review of current findings, caveats and future directions. OBM Genet. 2, 039 (2018).
Turecki, G. & Brent, D. A. Suicide and suicidal behaviour. Lancet 387, 1227–1239 (2016).
Bell, J. T. et al. Epigenome-wide scans identify differentially methylated regions for age and age-related phenotypes in a healthy ageing population. PLoS Genet. 8, e1002629 (2012).
pubmed: 22532803
pmcid: 3330116
Feil, R. & Fraga, M. F. Epigenetics and the environment: emerging patterns and implications. Nat. Rev. Genet. 13, 97–109 (2012).
pubmed: 22215131
Burns, S. B., Szyszkowicz, J. K., Luheshi, G. N., Lutz, P. E. & Turecki, G. Plasticity of the epigenome during early-life stress. Semin. Cell Dev. Biol. 77, 115–132 (2018).
pubmed: 29017800
Mill, J. & Heijmans, B. T. From promises to practical strategies in epigenetic epidemiology. Nat. Rev. Genet. 14, 585–594 (2013).
pubmed: 23817309
Wong, C. C. et al. Methylomic analysis of monozygotic twins discordant for autism spectrum disorder and related behavioural traits. Mol. Psychiatry 19, 495–503 (2014).
pubmed: 23608919
Pidsley, R. et al. Methylomic profiling of human brain tissue supports a neurodevelopmental origin for schizophrenia. Genome Biol. 15, 483 (2014).
pubmed: 25347937
pmcid: 4262979
Uddin, M. et al. Epigenetic and immune function profiles associated with posttraumatic stress disorder. Proc. Natl Acad. Sci. USA 107, 9470–9475 (2010).
pubmed: 20439746
Fisher, H. L. et al. Methylomic analysis of monozygotic twins discordant for childhood psychotic symptoms. Epigenetics 10, 1014–1023 (2015).
pubmed: 26479702
pmcid: 4867769
Murphy, T. M. et al. Anxiety is associated with higher levels of global DNA methylation and altered expression of epigenetic and interleukin-6 genes. Psychiatr. Genet. 25, 71–78 (2015).
pubmed: 25350786
Dempster, E. L. et al. Genome-wide methylomic analysis of monozygotic twins discordant for adolescent depression. Biol. Psychiatry 76, 977–983 (2014).
pubmed: 24929637
pmcid: 4252163
Davies, M. N. et al. Hypermethylation in the ZBTB20 gene is associated with major depressive disorder. Genome Biol. 15, R56 (2014).
pubmed: 24694013
pmcid: 4072999
Uddin, M. et al. Epigenetic and inflammatory marker profiles associated with depression in a community-based epidemiologic sample. Psychol. Med. 41, 997–1007 (2011).
pubmed: 20836906
Murphy, T. M. et al. Methylomic profiling of cortex samples from completed suicide cases implicates a role for PSORS1C3 in major depression and suicide. Transl. Psychiatry 7, e989 (2017).
pubmed: 28045465
pmcid: 5545719
Murphy, T. M. et al. Genetic variation in DNMT3B and increased global DNA methylation is associated with suicide attempts in psychiatric patients. Genes Brain Behav. 12, 125–132 (2013).
pubmed: 23025623
Labonte, B. et al. Genome-wide epigenetic regulation by early-life trauma. Arch. Gen. Psychiatry 69, 722–731 (2012).
pubmed: 22752237
pmcid: 4991944
Ernst, C. et al. Alternative splicing, methylation state, and expression profile of tropomyosin-related kinase B in the frontal cortex of suicide completers. Arch. Gen. Psychiatry 66, 22–32 (2009).
pubmed: 19124685
Fiori, L. M. & Turecki, G. Epigenetic regulation of spermidine/spermine N1-acetyltransferase (SAT1) in suicide. J. Psychiatr. Res 45, 1229–1235 (2011).
pubmed: 21501848
Keller, S. et al. Increased BDNF promoter methylation in the Wernicke area of suicide subjects. Arch. Gen. Psychiatry 67, 258–267 (2010).
pubmed: 20194826
Haghighi, F. et al. Increased DNA methylation in the suicide brain. Dialogues Clin. Neurosci. 16, 430–438 (2014).
pubmed: 25364291
pmcid: 4214183
Fiori, L. M., Gross, J. A. & Turecki, G. Effects of histone modifications on increased expression of polyamine biosynthetic genes in suicide. Int. J. Neuropsychopharmacol. 15, 1161–1166 (2012).
pubmed: 22008221
Maussion, G. et al. Functional DNA methylation in a transcript specific 3’UTR region of TrkB associates with suicide. Epigenetics 9, 1061–1070 (2014).
pubmed: 24802768
pmcid: 4164491
Kozlenkov, A. et al. DNA methylation profiling of human prefrontal cortex neurons in heroin users shows significant difference between genomic contexts of hyper- and hypomethylation and a younger epigenetic age. Genes (Basel) 8, 152 (2017).
Guintivano, J., Aryee, M. J. & Kaminsky, Z. A. A cell epigenotype specific model for the correction of brain cellular heterogeneity bias and its application to age, brain region and major depression. Epigenetics 8, 290–302 (2013).
pubmed: 23426267
pmcid: 3669121
Viana, J. et al. Schizophrenia-associated methylomic variation: molecular signatures of disease and polygenic risk burden across multiple brain regions. Hum. Mol. Genet. 26, 210–225 (2017).
pubmed: 28011714
Pidsley, R. et al. A data-driven approach to preprocessing Illumina 450K methylation array data. BMC Genomics 14, 293 (2013).
pubmed: 23631413
pmcid: 3769145
Price, M. E. et al. Additional annotation enhances potential for biologically-relevant analysis of the Illumina Infinium HumanMethylation450 BeadChip array. Epigenet. Chromatin 6, 4 (2013).
Chen, Y. A. et al. Discovery of cross-reactive probes and polymorphic CpGs in the Illumina Infinium HumanMethylation450 microarray. Epigenetics 8, 203–209 (2013).
pubmed: 23314698
pmcid: 23314698
Sarkar, D. Multivariate Data Visualization with R. http://lmdvr.r-forge.r-project.org . Accessed 2008 (2008).
Hannon, E. et al. An integrated genetic-epigenetic analysis of schizophrenia: evidence for co-localization of genetic associations and differential DNA methylation. Genome Biol. 17, 176 (2016).
pubmed: 27572077
pmcid: 5004279
Pedersen, B. S., Schwartz, D. A., Yang, I. V. & Kechris, K. J. Comb-p: software for combining, analyzing, grouping and correcting spatially correlated P-values. Bioinformatics 28, 2986–2988 (2012).
pubmed: 22954632
pmcid: 3496335
Šidák, Z. Rectangular confidence regions for the means of multivariate normal distributions. J. Am. Stat. Assoc. 62, 626–633 (1967).
Lunnon, K. et al. Variation in 5-hydroxymethylcytosine across human cortex and cerebellum. Genome Biol. 17, 27 (2016).
pubmed: 26883014
pmcid: 4756397
Rydbirk, R. et al. Assessment of brain reference genes for RT-qPCR studies in neurodegenerative diseases. Sci. Rep. 6, 37116 (2016).
pubmed: 27853238
pmcid: 5112547
Pfaffl, M. W. A new mathematical model for relative quantification in real-time RT-PCR. Nucleic Acids Res. 29, e45 (2001).
pubmed: 11328886
pmcid: 55695
Rehli, M. K. M. Functional analysis of promoter CPG-methylation using a CpG-free luciferase reporter vector. Epigenetics 1, 4 (2006).
Jacobs, J. L. & Dinman, J. D. Systematic analysis of bicistronic reporter assay data. Nucleic Acids Res. 32, e160 (2004).
pubmed: 15561995
pmcid: 534638
Abdelrahman, H. A., Al-Shamsi, A. M., Ali, B. R. & Al-Gazali, L. A null variant in PUS3 confirms its involvement in intellectual disability and further delineates the associated neurodevelopmental disease. Clin. Genet. 94, 586–587 (2018).
pubmed: 30308082
Klug, M. & Rehli, M. Functional analysis of promoter CPGmethylation using a CpG-free luciferase reporter vector. Epigenetics 1, 127–130 (2006).
pubmed: 17965610
Consortium, G. T. The Genotype-Tissue Expression (GTEx) project. Nat. Genet. 45, 580–585 (2013).
Schneider, E., El Hajj, N., Muller, F., Navarro, B. & Haaf, T. Epigenetic dysregulation in the prefrontal cortex of suicide completers. Cytogenet. Genome Res 146, 19–27 (2015).
pubmed: 26160260
Nagy, C. et al. Astrocytic abnormalities and global DNA methylation patterns in depression and suicide. Mol. Psychiatry 20, 320–328 (2015).
pubmed: 24662927
Nagy, C., Torres-Platas, S. G., Mechawar, N. & Turecki, G. Repression of astrocytic connexins in cortical and subcortical brain regions and prefrontal enrichment of H3K9me3 in depression and suicide. Int. J. Neuropsychopharmacol. 20, 50–57 (2017).
pubmed: 27516431
Phillips, J. R., Hewedi, D. H., Eissa, A. M. & Moustafa, A. A. The cerebellum and psychiatric disorders. Front. Public Health 3, 66 (2015).
pubmed: 26000269
pmcid: 4419550
Hwang, J. P. et al. Cortical and subcortical abnormalities in late-onset depression with history of suicide attempts investigated with MRI and voxel-based morphometry. J. Geriatr. Psychiatry Neurol. 23, 171–184 (2010).
pubmed: 20430976
Amen, D. G., Prunella, J. R., Fallon, J. H., Amen, B. & Hanks, C. A comparative analysis of completed suicide using high resolution brain SPECT imaging. J. Neuropsychiatry Clin. Neurosci. 21, 430–439 (2009).
pubmed: 19996252
Lee, Y. J. et al. Decreased regional gray matter volume in suicide attempters compared to suicide non-attempters with major depressive disorders. Compr. Psychiatry 67, 59–65 (2016).
pubmed: 27095336
Jung, J. et al. Alterations in functional brain networks in depressed patients with a suicide attempt history. Neuropsychopharmacology. https://doi.org/10.1038/s41386-019-0560-z (2019).
Stawski, R. et al. Reduced expression of ELAVL4 in male meningioma patients. Brain Tumor Pathol. 30, 160–166 (2013).
pubmed: 22965691
Akamatsu, W. et al. The RNA-binding protein HuD regulates neuronal cell identity and maturation. Proc. Natl Acad. Sci. USA 102, 4625–4630 (2005).
pubmed: 15764704
Ince-Dunn, G. et al. Neuronal Elav-like (Hu) proteins regulate RNA splicing and abundance to control glutamate levels and neuronal excitability. Neuron 75, 1067–1080 (2012).
pubmed: 22998874
pmcid: 3517991
Talman, V., Pascale, A., Jantti, M., Amadio, M. & Tuominen, R. K. Protein kinase C activation as a potential therapeutic strategy in Alzheimer’s disease: is there a role for embryonic lethal abnormal vision-like proteins? Basic Clin. Pharm. Toxicol. 119, 149–160 (2016).
Yamada, K. et al. Genome-wide association study of schizophrenia in Japanese population. PLoS ONE 6, e20468 (2011).
pubmed: 21674006
pmcid: 3108953
Berto, S., Usui, N., Konopka, G. & Fogel, B. L. ELAVL2-regulated transcriptional and splicing networks in human neurons link neurodevelopment and autism. Hum. Mol. Genet. 25, 2451–2464 (2016).
pubmed: 27260404
pmcid: 6086562
de Paiva, A. R. B. et al. PUS3 mutations are associated with intellectual disability, leukoencephalopathy, and nephropathy. Neurol. Genet. 5, e306 (2019).
pubmed: 30697592
pmcid: 6340380
Yokota, N. et al. Predominant expression of human zic in cerebellar granule cell lineage and medulloblastoma. Cancer Res. 56, 377–383 (1996).
pubmed: 8542595
pmcid: 8542595
Vitucci, D. et al. Rasd2 modulates prefronto-striatal phenotypes in humans and ‘schizophrenia-like behaviors’ in mice. Neuropsychopharmacology 41, 916–927 (2016).
pubmed: 26228524
Sun, H. et al. Quantitative integration of epigenomic variation and transcription factor binding using MAmotif toolkit identifies an important role of IRF2 as transcription activator at gene promoters. Cell Discov. 4, 38 (2018).
pubmed: 30002873
pmcid: 6037672
Drew, P. D. et al. Interferon regulatory factor-2 physically interacts with NF-kappa B in vitro and inhibits NF-kappa B induction of major histocompatibility class I and beta 2-microglobulin gene expression in transfected human neuroblastoma cells. J. Neuroimmunol. 63, 157–162 (1995).
pubmed: 8550813
Daniele, L. L., Emran, F., Lobo, G. P., Gaivin, R. J. & Perkins, B. D. Mutation of wrb, a component of the guided entry of tail-anchored protein pathway, disrupts photoreceptor synapse structure and function. Invest. Ophthalmol. Vis. Sci. 57, 2942–2954 (2016).
pubmed: 27273592
pmcid: 4898200
Ling, K. H. et al. Functional transcriptome analysis of the postnatal brain of the Ts1Cje mouse model for Down syndrome reveals global disruption of interferon-related molecular networks. BMC Genomics 15, 624 (2014).
pubmed: 25052193
pmcid: 4124147
Nair, R. P. et al. Sequence and haplotype analysis supports HLA-C as the psoriasis susceptibility 1 gene. Am. J. Hum. Genet. 78, 827–851 (2006).
pubmed: 16642438
pmcid: 1474031
Chang, Y. T. et al. Psoriasis vulgaris in Chinese individuals is associated with PSORS1C3 and CDSN genes. Br. J. Dermatol. 155, 663–669 (2006).
pubmed: 16965413
Wisniewski, A., Matusiak, L., Szczerkowska-Dobosz, A., Nowak, I. & Kusnierczyk, P. HLA-C*06:02-independent, gender-related association of PSORS1C3 and PSORS1C1/CDSN single-nucleotide polymorphisms with risk and severity of psoriasis. Mol. Genet. Genomics 293, 957–966 (2018).
pubmed: 29589160
pmcid: 6061044
Polanowska, J. et al. The periodic down regulation of Cyclin E gene expression from exit of mitosis to end of G(1) is controlled by a deacetylase- and E2F-associated bipartite repressor element. Oncogene 20, 4115–4127 (2001).
pubmed: 11464278
Yamada, K. et al. Population-dependent contribution of the major histocompatibility complex region to schizophrenia susceptibility. Schizophr. Res. 168, 444–449 (2015).
pubmed: 26324334
Pfleger, C. M. The Hippo pathway: a master regulatory network important in development and dysregulated in disease. Curr. Top. Dev. Biol. 123, 181–228 (2017).
pubmed: 28236967
Sun, R. et al. Identification of novel loci associated with infant cognitive ability. Mol. Psychiatry. https://doi.org/10.1038/s41380-018-0205-3 (2018).
Hamdan, F. F. et al. De novo mutations in moderate or severe intellectual disability. PLoS Genet. 10, e1004772 (2014).
pubmed: 25356899
pmcid: 4214635
Nizon, M. et al. Variants in MED12L, encoding a subunit of the mediator kinase module, are responsible for intellectual disability associated with transcriptional defect. Genet. Med. 21, 2713–2722 (2019).
Branco, M. R., Ficz, G. & Reik, W. Uncovering the role of 5-hydroxymethylcytosine in the epigenome. Nat. Rev. Genet. 13, 7–13 (2011).
pubmed: 22083101
pmcid: 22083101
Clive, M. L. et al. Discovery and replication of a peripheral tissue DNA methylation biosignature to augment a suicide prediction model. Clin. Epigenet. 8, 113 (2016).
Sadeh, N. et al. Epigenetic Variation at Ska2 Predicts Suicide Phenotypes and Internalizing Psychopathology. Depress Anxiety 33, 308–315 (2016).
pubmed: 27038412
pmcid: 4825872
Kaminsky, Z. et al. Epigenetic and genetic variation at SKA2 predict suicidal behavior and post-traumatic stress disorder. Transl. Psychiatry 5, e627 (2015).
pubmed: 26305478
pmcid: 4564560
Lockwood, L. E., Su, S. & Youssef, N. A. The role of epigenetics in depression and suicide: a platform for gene-environment interactions. Psychiatry Res 228, 235–242 (2015).
pubmed: 26163724
Guintivano, J. et al. Identification and replication of a combined epigenetic and genetic biomarker predicting suicide and suicidal behaviors. Am. J. Psychiatry 171, 1287–1296 (2014).
pubmed: 25073599
pmcid: 7081376