The addition of a methyl group to, typically, a cytosine-guanine dinucleotide (CpG) creates distinct DNA methylation patterns across the genome that can regulate gene expression. Aberrant DNA methylation of CpG sites has been associated with many psychiatric disorders including bipolar disorder (BD) and suicide. Using the SureSelectXT system, Methyl-Seq, we investigated the DNA methylation status of CpG sites throughout the genome in 50 BD individuals (23 subjects who died by suicide and 27 subjects who died from other causes) and 31 nonpsychiatric controls. We identified differentially methylated regions (DMRs) from three analyses: (a) BD subjects compared to nonpsychiatric controls (BD-NC), (b) BD subjects who died by suicide compared to nonpsychiatric controls (BDS-NC), and (c) BDS subjects compared to BD subjects who died from other causes (BDS-BDNS). One DMR from the BDS-NC analysis, located in ARHGEF38, was significantly hypomethylated (23.4%) in BDS subjects. This finding remained significant after multiple testing (PBootstrapped = 9.0 × 10-3 ), was validated using pyrosequencing, and was more significant in males. A secondary analysis utilized Ingenuity Pathway Analysis to identify enrichment in nominally significant DMRs. This identified an association with several pathways including axonal guidance signaling, calcium signaling, β-adrenergic signaling, and opioid signaling. Our comprehensive study provides further support that DNA methylation alterations influence the risk for BD and suicide. However, further investigation is required to confirm these associations and identify their functional consequences.

中文翻译：

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双相情感障碍和自杀中的差异甲基化区域。

通常，向胞嘧啶-鸟嘌呤二核苷酸 (CpG) 添加甲基会在整个基因组中产生不同的 DNA 甲基化模式，可以调节基因表达。CpG 位点的异常 DNA 甲基化与许多精神疾病有关，包括双相情感障碍 (BD) 和自杀。使用 SureSelectXT 系统 Methyl-Seq，我们调查了 50 名 BD 个体（23 名死于自杀的受试者和 27 名死于其他原因的受试者）和 31 名非精神病对照者的整个基因组中 CpG 位点的 DNA 甲基化状态。我们从三个分析中确定了差异甲基化区域 (DMR)：(a) BD 受试者与非精神病对照 (BD-NC) 相比，(b) 与非精神病对照 (BDS-NC) 相比死于自杀的 BD 受试者，(c) BDS 受试者与死于其他原因的 BD 受试者 (BDS-BDNS) 的比较。来自 BDS-NC 分析的一个 DMR 位于 ARHGEF38，在 BDS 受试者中显着低甲基化（23.4%）。这一发现在多次测试后仍然显着（PBootstrapped = 9.0 × 10-3 ），使用焦磷酸测序进行验证，并且在男性中更显着。二次分析利用 Ingenuity Pathway Analysis 来确定名义上显着的 DMR 的富集。这确定了与几种途径的关联，包括轴突引导信号、钙信号、β-肾上腺素能信号和阿片类信号。我们的综合研究进一步支持 DNA 甲基化改变影响 BD 和自杀的风险。但是，需要进一步调查以确认这些关联并确定其功能后果。