Methylome-wide association findings for major depressive disorder overlap in blood and brain and replicate in independent brain samples.
Methylome-wide association findings for major depressive disorder overlap in blood and brain and replicate in independent brain samples.
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DOI：
10.1038/s41380-018-0247-6
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发表时间：
2020-06
影响因子：
11
通讯作者：
van den Oord EJCG
中科院分区：
文献类型：
--
作者：
Aberg KA;Dean B;Shabalin AA;Chan RF;Han LKM;Zhao M;van Grootheest G;Xie LY;Milaneschi Y;Clark SL;Turecki G;Penninx BWJH;van den Oord EJCG
我们首次对重性抑郁症（MDD）进行大规模的全甲基化关联研究（MWAS），以确定MDD病因的潜在重要性。使用一种基于测序的方法，几乎完全覆盖了人类基因组中所有2800万个常见的CpG，我们分析了MDD病例和血液（N= 1，132）和死后脑组织（N=61个来自Brodmann Area 10，BA 10）的对照组中的甲基化。血液的MWAS识别出了几个P值为1.91×10−8-4.39×10−8的基因座，而一种回归方法显示，来自前25，000个MWAS标记的信号具有显著的累积相关性（P=4.03×10−10）。此外，基于排列的分析显示，血液和脑（BA 10）中的MWAS结果之间存在显著重叠（P=5.4×10−3）。这种重叠显著富集了许多特征，包括在血液和额叶皮质中的eQTL、CpG岛和海岸以及外显子中。重叠位点也富集了脑中的活性染色质状态，包括基因增强子和活性转录起始位点。此外，位于GABBR 2，RUFY 3和2号染色体上的基因间区域的三个位点在来自相同个体的第二脑组织（BA 25，N=60）和两个独立的脑集合（BA 10，N=81和64）中以相同的方向复制。GABBR 2通过G蛋白偶联的第二信使系统抑制神经元活性，RUFY 3涉及神经元极性的建立和轴突伸长。总之，我们确定并复制了与MDD相关的甲基化位点，这些位点参与了可能对MDD病因重要的生物学功能。
We present the first large-scale methylome-wide association studies (MWAS) for major depressive disorder (MDD) to identify sites of potential importance for MDD etiology. Using a sequencing-based approach that provides near-complete coverage of all 28 million common CpGs in the human genome, we assay methylation in MDD cases and controls from both blood (N=1,132) and postmortem brain tissues (N=61 samples from Brodmann Area 10, BA10). The MWAS for blood identified several loci with P 1.91×10−8-4.39×10−8 and a resampling approach showed that the cumulative association was significant (P=4.03×10−10) with the signal coming from the top 25,000 MWAS markers. Furthermore, a permutation based analysis showed significant overlap (P=5.4×10−3) between the MWAS findings in blood and brain (BA10). This overlap was significantly enriched for a number of features including being in eQTLs in blood and frontal cortex, CpG islands and shores, and exons. The overlapping sites were also enriched for active chromatin states in brain including genic enhancers and active transcription start sites. Furthermore, three loci located in GABBR2, RUFY3 and in an intergenic region on chromosome 2 replicated with the same direction of effect in the second brain tissue (BA25, N=60) from the same individuals and in two independent brain collections (BA10, N=81 and 64). GABBR2 inhibits neuronal activity through G protein-coupled second-messenger systems and RUFY3 is implicated in the establishment of neuronal polarity and axon elongation. In conclusion, we identified and replicated methylated loci associated with MDD that are involved in biological functions of likely importance to MDD etiology.
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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
影响因子：
6.6
作者：
Gibbons, Andrew Stuart;Brooks, Lucy;Scarr, Elizabeth;Dean, Brian
通讯作者：
Dean, Brian
影响因子：
3.7
作者：
Aberg, Karolina A.;Chan, Robin F.;van den Oord, Edwin J. C. G.
通讯作者：
van den Oord, Edwin J. C. G.
影响因子：
3.6
作者：
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通讯作者：
Eicher, Eva M.
影响因子：
6.7
作者：
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通讯作者：
Duberstein, PR