Investigation of correlations between DNA methylation, suicidal behavior and aging.

OBJECTIVES:Suicidal behavior (SB) is a major cause of mortality for patients diagnosed with bipolar disorder (BD). In this study, we investigated epigenetic differences in BD participants with and without a history of SB. METHODS:We used suicidality scores constructed from Schedule for Clinical Assessments in Neuropsychiatry (SCAN) interview questions about suicidal thought and behavior to identify individuals from a BD cohort of n=452; participants with the most extreme high (H-SB, n=18) and most extreme low (L-SB, n=22) scores were used as cases and controls, respectively. Epigenome-wide DNA methylation patterns were compared between the two groups using the Illumina Infinium Human Methylation 450 BeadChip microarray. DNA methylation age was compared to chronological tissue age. RESULTS:We observed highly significant differences in methylation between cases and controls in three genomic regions enriched for epigenetic modifications corresponding to gene regulatory regions. BD participants with a history of SB showed less overall methylation in the 5' untranslated region of Membrane palmitoylated protein 4 (MPP4) (P=7.42×10(-7) ) and in intron 3 of TRE2/BUB2/CDC16 domain family member 16 (TBC1D16) (P=6.47×10(-7) ), while exon 1 of Nucleoporin 133 (NUP133) was less methylated in controls (P=1.17x10(-6) ). Moreover, we observed a greater correlation between DNA methylation age and tissue age in controls (r=.91, P<.0001) than in the H-SB group (r=.83, P<.0001). CONCLUSIONS:We report significant findings at three loci based on a methylome scan of participants with BD for an SB phenotype, and potentially altered molecular aging in suicide attempters. Despite the small sample size, our proof-of-concept study highlights the potential for epigenetic factors to be useful in understanding the molecular underpinnings of suicide with the ultimate aim of its prevention.

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