Investigation of correlations between DNA methylation, suicidal behavior and aging

Jeremian, Richie; Chen, Yi‐An; Luca, Vincenzo De; Vincent, John B.; Kennedy, James L.; Zai, Clement C.; Strauss, John S.

doi:10.1111/bdi.12466

Cited by 30 publications

(22 citation statements)

References 56 publications

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“…The third gene identified for EAs with gene-based association analysis was PGBD5 ; it maps 5 MB from “Nucleoporin 133” ( NUP133 ); the latter locus was epigenome-wide significant in a study using a quantitative suicidality score 37 . Although the authors of that study focused more on NUP133 , PGBD5 was discussed for its proximity to top findings and overlap with findings in panic-induced epigenetic H3K27me3 modifications in mice 38 .…”

Section: Discussionmentioning

confidence: 99%

“…In summary, we identified several associations in genes or associated pathways that have previously been implicated in suicide. Epigenetic modifications near PGBD5 and NUP133 have been associated with quantitative scores for suicidality 37 . Suicidal ideation state changes have been associated with the increased expression of PHLDB2 in independent studies in men 36 and women 35 .…”

Section: Discussionmentioning

confidence: 99%

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Genetic associations with suicide attempt severity and genetic overlap with major depression

et al. 2019

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In 2015, ~800,000 people died by suicide worldwide. For every death by suicide there are as many as 25 suicide attempts, which can result in serious injury even when not fatal. Despite this large impact on morbidity and mortality, the genetic influences on suicide attempt are poorly understood. We performed a genome-wide association study (GWAS) of severity of suicide attempts to investigate genetic influences. A discovery GWAS was performed in Yale-Penn sample cohorts of European Americans (EAs, n = 2,439) and African Americans (AAs, n = 3,881). We found one genome-wide significant (GWS) signal in EAs near the gene LDHB (rs1677091, p = 1.07 × 10−8) and three GWS associations in AAs: ARNTL2 on chromosome 12 (rs683813, p = 2.07 × 10−8), FAH on chromosome 15 (rs72740082, p = 2.36 × 10−8), and on chromosome 18 (rs11876255, p = 4.61 × 10−8) in the Yale-Penn discovery sample. We conducted a limited replication analysis in the completely independent Army-STARRS cohorts. rs1677091 replicated in Latinos (LAT, p = 6.52 × 10−3). A variant in LD with FAH rs72740082 (rs72740088; r2 = 0.68) was replicated in AAs (STARRS AA p = 5.23 × 10−3; AA meta, 1.51 × 10−9). When combined for a trans-population meta-analysis, the final sample size included n = 20,153 individuals. Finally, we found significant genetic overlap with major depressive disorder (MDD) using polygenic risk scores from a large GWAS (r2 = 0.007, p = 6.42 × 10−5). To our knowledge, this is the first GWAS of suicide attempt severity. We identified GWS associations near genes involved in anaerobic energy production (LDHB), circadian clock regulation (ARNTL2), and catabolism of tyrosine (FAH). These findings provide evidence of genetic risk factors for suicide attempt severity, providing new information regarding the molecular mechanisms involved.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Genetic associations with suicide attempt severity and genetic overlap with major depression

et al. 2019

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“…Some studies have shown a possible role of modified expression of such genes as MPP4 (membrane palmitoylated protein 4), nucleoporin (NUP133), a member of the TRE2/ BuB2/CDC16 family of domains (TBC1D16), the alpha1 subunit of the gamma-aminobutyric acid receptor (GABRA1) in SB development. In particular, a total decrease in methylation in the 5′-UTR of the MPP4 gene and in intron 3 of the TBC1D16 gene together with increased methylation in exon 1 of the NUP133 gene was observed in patients with bipolar disorder and comorbid SB compared to the control group (Jeremian et al, 2017). In addition, hypermethylation of CpG islands in the promoter of the GABRA1 gene was associated with changes in mRNA expression of the DNA methyltransferase gene (DNMT) in the brain of individuals with completed suicide (Poulter et al, 2008).…”

Section: Changes In Dna Methylation and Histone Modificationmentioning

confidence: 93%

Epigenetics of suicidal behavior

et al. 2019

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Suicide is the second leading cause of death among young people and therefore being a serious global problem worldwide. The study of genetic and epigenetic factors in the development of suicidal behavior plays an important role in the development of advanced methods of diagnosis and treatment of this pathology. The role of hereditary factors in the development of suicidal behavior is estimated at 30–55 %, with a pronounced comorbidity with other psychopathologies. The study of genetic liability to suicidal behavior is based on molecular-genetic methods including association and linkage analyses, chip gene expression arrays, and genome-wide association studies. Published data identified multiple genes including those involved in the functioning of serotonergic (SLC6A4, TPH, 5-HT1A), hypothalamic-pituitary-adrenal systems (FKBP5) and polyamines (SAT and OATL1) associated with suicidal behavior. However, the diversity of interacting genetic loci complicates the interpretation of the development of a complex phenotype of pathology and prevents the association from being detected. To solve this problem and interpret the missing relationship between the environment and the genome, promising results were obtained from a study of epigenetic factors, which affected the expression of a number of candidate genes involved in brain functioning in suicidal behavior. The analysis of a brain obtained from suicide victims, representing a unique tool for the analysis of modified genomic processes, revealed a wide range of reprogramming patterns of DNA methylation in promoters of the genes of polyamine (OAZ1, OAZ2, AMD1, ARG2, SKA2), serotonergic (SLC6A4) and GABAergic (GABRA1) systems, HPA-axis (GR, NR3C1), tyrosine kinase (TrkB) receptors, brain-derived neurotrophic factor (BDNF). The role of histone modifications in distinct genes (Cx30, Cx43, TrkB.T1) and the expression of specific long noncoding RNAs and microRNAs in the development of suicidal behavior, which is promising for the development of diagnostic algorithms and target therapy, is discussed.

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“…In a study researchers compared blood methylation profile between patients with bipolar disorder showing suicidal behaviour and patients who showed no such behaviour. They as well observed differential levels of methylation of multiple genome regions in patients with suicidal behaviour, identifying three potential candidate genes (Jeremian et al 2017). One of the biggest studies so far observed methylation levels in blood and a subset sample of prefrontal cortex in patients with major depressive disorder.…”

Section: Suicidal Behaviour and Genome-wide Dna Methylation Studiesmentioning

confidence: 99%

Genome-Wide Dna Methylation Patterns in Suicide Victims: Identification of New Candidate Genes

Kouter

Zupanc²,

Paska³

2019

Psychiat Danub

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Suicide is a major global public health problem with significant impact on society. According to the World Health Organization, every year about 800.000 people commit suicide, while at the global level suicide accounts for 50 % of all violent deaths among men and for 71 % among women. Suicide is a complex phenomenon which cannot be attributed to a single causal factor, but to a combination of simultaneous effects of multiple factors which are expressed in the form of psychological, biological and sociological indicators. Analysis of epigenetic mechanisms (methylation of the DNA, modifications of histone proteins and (networks of) miRNA), which link the interaction between genes and the environment, could importantly contribute to better understanding of suicidal behaviour. Recent studies on suicidal behaviour and DNA methylation show differences in DNA methylation pattern, with numerous sites among suicide victims. Using next generation sequencing, genome-wide studies helped identify novel candidate genes while studies of already known candidate genes (such as glucocorticoid receptor and BDNF) gave us better insight into the interplay of genetics and epigenetics.Epigenetic studies importantly contribute to elucidation of new biomarkers for suicidal behaviour. However, present studies are very different in design and often performed on very small samples, and these limitations could be overcome with more careful study preparation.

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Investigation of correlations between DNA methylation, suicidal behavior and aging

Cited by 30 publications

References 56 publications

Genetic associations with suicide attempt severity and genetic overlap with major depression

Genetic associations with suicide attempt severity and genetic overlap with major depression

Epigenetics of suicidal behavior

Genome-Wide Dna Methylation Patterns in Suicide Victims: Identification of New Candidate Genes

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