Department of Psychiatry, University of Iowa Carver College of Medicine, Iowa City, Iowa.
Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore, Maryland.
Am J Med Genet B Neuropsychiatr Genet. 2019 Oct;180(7):496-507. doi: 10.1002/ajmg.b.32754. Epub 2019 Jul 27.
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 SureSelect 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 (P = 9.0 × 10 ), 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.
通常情况下，在胞嘧啶-鸟嘌呤二核苷酸（CpG）上添加一个甲基基团会在整个基因组中产生独特的 DNA 甲基化模式，从而调节基因表达。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 SureSelect 系统，Methyl-Seq，我们研究了 50 名 BD 个体（23 名自杀死亡和 27 名其他原因死亡）和 31 名非精神病对照者整个基因组中 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 患者与非精神病对照者（BD-NC）相比，（b）BD 患者自杀与非精神病对照者（BDS-NC）相比，（c）BDS 患者与 BD 患者死于其他原因（BDS-BDNS）相比。BDS-NC 分析中的一个 DMR，位于 ARHGEF38 中，BDS 患者明显低甲基化（23.4%）。经过多次测试（P = 9.0×10），该发现仍然显著，使用焦磷酸测序进行验证，并在男性中更为显著。二次分析利用基因通路分析识别了名义上显著的 DMR 中的富集。这确定了与几个途径的关联，包括轴突导向信号、钙信号、β-肾上腺素能信号和阿片信号。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。然而，需要进一步的研究来确认这些关联，并确定它们的功能后果。
