DNA methylation in a Scottish family multiply affected by bipolar disorder and major depressive disorder.
DNA methylation in a Scottish family multiply affected by bipolar disorder and major depressive disorder.
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DOI：
10.1186/s13148-016-0171-z
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发表时间：
2016
影响因子：
5.7
通讯作者：
Evans KL
中科院分区：
文献类型：
--
作者：
Walker RM;Christoforou AN;McCartney DL;Morris SW;Kennedy NA;Morten P;Anderson SM;Torrance HS;Macdonald A;Sussmann JE;Whalley HC;Blackwood DH;McIntosh AM;Porteous DJ;Evans KL
双相情感障碍是一种严重的家族性精神疾病。了解双相障碍病因的进展一直受到大量表型和遗传异质性的阻碍。我们试图通过研究一个受双相障碍和重度抑郁症（MDD）影响的多代家族来减轻这些混杂因素，他们在染色体4p上携带疾病相关的单倍型。在一个家庭中，病因异质性可能会减少，从而赋予更大的权力来检测与疾病相关的变化。越来越多的证据表明，DNA甲基化改变会增加BD和MDD的风险，我们比较了(i)受影响的连锁单倍型携带者（ALH）和已婚对照（MIs）， （ii）未受影响的单倍型携带者（ULH）和MI， （iii） ALH和ULH以及（iv）所有单倍型携带者（LH）和MI之间的全基因组甲基化。在所有比较中，表面上都观察到DNA甲基化的显著差异。当将ALH或LH组与MIs进行比较时，差异经受多次测试的校正。在这两种比较中，我们观察到FANCI基因座甲基化增加，这伴随着ALH组FANCI表达增加。FANCI是范可尼贫血补体（Fanconi anemia complemententation， FANC）基因家族的一部分，在范可尼贫血中发生突变，参与DNA修复。有趣的是，一些FANC基因与精神疾病有关。甲基化差异的区域分析通过全基因组关联研究确定了与精神疾病相关的位点，包括CACNB2和主要组织相容性复合体。基因本体分析显示神经相关基因的甲基化差异富集。我们的研究结果强调，DNA甲基化改变是一种潜在的机制，通过这种机制，相关的单倍型可能会导致情绪障碍的风险。单倍型携带者在表型结果上的差异可能部分源于DNA甲基化的额外变化，这些变化集中在神经学上重要的通路上。需要进一步的工作来研究甲基化差异的潜在机制和功能后果。本文的在线版本（doi:10.1186/s13148-016-0171-z）包含补充材料，可供授权用户使用。
Bipolar disorder (BD) is a severe, familial psychiatric condition. Progress in understanding the aetiology of BD has been hampered by substantial phenotypic and genetic heterogeneity. We sought to mitigate these confounders by studying a multi-generational family multiply affected by BD and major depressive disorder (MDD), who carry an illness-linked haplotype on chromosome 4p. Within a family, aetiological heterogeneity is likely to be reduced, thus conferring greater power to detect illness-related changes. As accumulating evidence suggests that altered DNA methylation confers risk for BD and MDD, we compared genome-wide methylation between (i) affected carriers of the linked haplotype (ALH) and married-in controls (MIs), (ii) well unaffected haplotype carriers (ULH) and MI, (iii) ALH and ULH and (iv) all haplotype carriers (LH) and MI. Nominally significant differences in DNA methylation were observed in all comparisons, with differences withstanding correction for multiple testing when the ALH or LH group was compared to the MIs. In both comparisons, we observed increased methylation at a locus in FANCI, which was accompanied by increased FANCI expression in the ALH group. FANCI is part of the Fanconi anaemia complementation (FANC) gene family, which are mutated in Fanconi anaemia and participate in DNA repair. Interestingly, several FANC genes have been implicated in psychiatric disorders. Regional analyses of methylation differences identified loci implicated in psychiatric illness by genome-wide association studies, including CACNB2 and the major histocompatibility complex. Gene ontology analysis revealed enrichment for methylation differences in neurologically relevant genes. Our results highlight altered DNA methylation as a potential mechanism by which the linked haplotype might confer risk for mood disorders. Differences in the phenotypic outcome of haplotype carriers might, in part, arise from additional changes in DNA methylation that converge on neurologically important pathways. Further work is required to investigate the underlying mechanisms and functional consequences of the observed differences in methylation. The online version of this article (doi:10.1186/s13148-016-0171-z) contains supplementary material, which is available to authorized users.