Preliminary assessment of pre-morbid DNA methylation in individuals at high genetic risk of mood disorders.
Preliminary assessment of pre-morbid DNA methylation in individuals at high genetic risk of mood disorders.
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情绪障碍高遗传风险个体病前 DNA 甲基化的初步评估。
DOI：
10.1111/bdi.12415
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发表时间：
2016
影响因子：
5.4
通讯作者：
Evans,KathrynLouise
中科院分区：
文献类型：
--
作者：
Walker,RosieMay;Sussmann,JessikaElizabeth;Whalley,HeatherClare;Ryan,NiamhMargaret;Porteous,DavidJohn;McIntosh,AndrewMark;Evans,KathrynLouise
目的越来越多的证据表明DNA甲基化改变与包括双相情感障碍（BD）和抑郁症（MDD）在内的精神疾病有关。然而，尚不清楚这些变化是病因还是疾病进展或治疗的结果。为了解开这些可能性，我们分析了情绪障碍家族风险高的无关个体的全基因组DNA甲基化。随后发展BD或MDD的个体之间的DNA甲基化进行了比较[后来（IL）]和那些保持良好的[后来（WL）]。MethodsDNA甲基化图谱从全血样本中获得22 IL和23 WL个人使用Infinium HumanMethylation 450微珠芯片。差异甲基化在单基因座和区域基础上进行评估。进行途径分析，以评估富集特定的生物过程中名义上显着差异甲基化的locis.ResultsAlthough没有位点经受多次测试的校正，uncorrectedP-值提供了提示性证据，改变甲基化的网站内的基因以前牵连在神经精神疾病，如转录因子4（TCF 4）和白细胞介素1受体辅助蛋白样1（[IL1RAPL1];P≤3.11×10−5）。通路分析显示几种神经学相关通路和功能显著富集，包括神经系统发育和功能与行为;这些结果经得起多次检验校正（q≤0.05）。对差异甲基化区域的分析在主要组织相容性复合体中发现了几个区域（P≤.000 479），该区域先前与精神分裂症和BD有关。结论我们的数据提供了临时证据，证明神经相关基因中全血DNA甲基化的改变与情绪障碍的病因有关。这些发现与全基因组关联研究的结果一致。
ObjectivesAccumulating evidence implicates altered DNA methylation in psychiatric disorders, including bipolar disorder (BD) and major depressive disorder (MDD). It is not clear, however, whether these changes are causative or result from illness progression or treatment. To disentangle these possibilities we profiled genome‐wide DNA methylation in well, unrelated individuals at high familial risk of mood disorder. DNA methylation was compared between individuals who subsequently developed BD or MDD [ill later (IL)] and those who remained well [well later (WL)].MethodsDNA methylation profiles were obtained from whole‐blood samples from 22 IL and 23 WL individuals using the Infinium HumanMethylation450 BeadChip. Differential methylation was assessed on a single‐locus and regional basis. Pathway analysis was performed to assess enrichment for particular biological processes amongst nominally significantly differentially methylated loci.ResultsAlthough no locus withstood correction for multiple testing, uncorrectedP‐values provided suggestive evidence for altered methylation at sites within genes previously implicated in neuropsychiatric conditions, such asTranscription Factor 4(TCF4) andInterleukin 1 Receptor Accessory Protein‐Like 1([IL1RAPL1];P≤3.11×10−5). Pathway analysis revealed significant enrichment for several neurologically relevant pathways and functions, includingNervous System Development and FunctionandBehavior; these findings withstood multiple testing correction (q≤0.05). Analysis of differentially methylated regions identified several within the major histocompatibility complex (P≤.000 479), a region previously implicated in schizophrenia and BD.ConclusionsOur data provide provisional evidence for the involvement of altered whole‐blood DNA methylation in neurologically relevant genes in the aetiology of mood disorders. These findings are convergent with the findings of genome‐wide association studies.