Methylomic profiling of cortex samples from completed suicide cases implicates a role for PSORS1C3 in major depression and suicide.
Methylomic profiling of cortex samples from completed suicide cases implicates a role for PSORS1C3 in major depression and suicide.
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DOI：
10.1038/tp.2016.249
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发表时间：
2017-01-03
影响因子：
6.8
通讯作者：
Mill J
中科院分区：
文献类型：
--
作者：
Murphy TM;Crawford B;Dempster EL;Hannon E;Burrage J;Turecki G;Kaminsky Z;Mill J
重度抑郁症（MDD）是一个主要的社会和经济健康问题，并构成自杀的主要危险因素。自杀性抑郁症的分子病理学仍然知之甚少，虽然它已被假设，调控基因组过程参与了MDD和自杀的病理学。在这项研究中，在抑郁症自杀完成者（n=20）中评估了DNA甲基化的全基因组模式，并使用来自两个皮质脑区域（Brodmann Area 11（BA11）和Brodmann Area 25（BA25））的组织与非精神病性猝死对照组（n=20）进行了比较。分析重点是确定差异甲基化区域（DMR）与自杀性抑郁症和表观遗传变异的背景下，探讨了抑郁症和自杀的多基因风险评分。采用加权基因共甲基化网络分析，确定与抑郁症自杀完成者相关的共甲基化位点模块，以及MDD和自杀企图的多基因负担。我们确定了PSORS1C3基因上游的DMR，随后使用亚硫酸氢盐焦磷酸测序进行了验证，并在第二组自杀样本中进行了复制，其特征在于MDD自杀病例中两个皮质脑区域的显著低甲基化。我们还确定了与自杀企图相关的多基因风险负担相关的共甲基化位点的离散模块，但与抑郁症无关。自杀相关的共甲基化模块在涉及与抑郁和自杀倾向相关的生物学过程的基因网络中富集，包括神经系统发育和线粒体功能。我们的数据表明，与自杀相关的DNA甲基化存在协调变化，这可能为抑郁自杀完成者相关的分子病理学提供新的见解。
Major depressive disorder (MDD) represents a major social and economic health issue and constitutes a major risk factor for suicide. The molecular pathology of suicidal depression remains poorly understood, although it has been hypothesised that regulatory genomic processes are involved in the pathology of both MDD and suicidality. In this study, genome-wide patterns of DNA methylation were assessed in depressed suicide completers (n=20) and compared with non-psychiatric, sudden-death controls (n=20) using tissue from two cortical brain regions (Brodmann Area 11 (BA11) and Brodmann Area 25 (BA25)). Analyses focused on identifying differentially methylated regions (DMRs) associated with suicidal depression and epigenetic variation were explored in the context of polygenic risk scores for major depression and suicide. Weighted gene co-methylation network analysis was used to identify modules of co-methylated loci associated with depressed suicide completers and polygenic burden for MDD and suicide attempt. We identified a DMR upstream of the PSORS1C3 gene, subsequently validated using bisulfite pyrosequencing and replicated in a second set of suicide samples, which is characterised by significant hypomethylation in both cortical brain regions in MDD suicide cases. We also identified discrete modules of co-methylated loci associated with polygenic risk burden for suicide attempt, but not major depression. Suicide-associated co-methylation modules were enriched among gene networks implicating biological processes relevant to depression and suicidality, including nervous system development and mitochondria function. Our data suggest that there are coordinated changes in DNA methylation associated with suicide that may offer novel insights into the molecular pathology associated with depressed suicide completers.
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影响因子：
10.6
作者：
Dempster EL;Wong CC;Lester KJ;Burrage J;Gregory AM;Mill J;Eley TC
通讯作者：
Eley TC
WGCNA：用于加权相关网络分析的 R 包。
影响因子：
3
作者：
Langfelder P;Horvath S
通讯作者：
Horvath S
影响因子：
25
作者：
Hannon E;Spiers H;Viana J;Pidsley R;Burrage J;Murphy TM;Troakes C;Turecki G;O'Donovan MC;Schalkwyk LC;Bray NJ;Mill J
通讯作者：
Mill J
影响因子：
10.5
作者：
Cabili, Moran N.;Trapnell, Cole;Rinn, John L.
通讯作者：
Rinn, John L.
影响因子：
10.3
作者：
Chang, Y. T.;Chou, C. T.;Tsai, S. F.
通讯作者：
Tsai, S. F.