Chen Li, Pan Hong, Tuan Ta Anh, Teh Ai Ling, MacIsaac Julia L, Mah Sarah M, McEwen Lisa M, Li Yue, Chen Helen, Broekman Birit F P, Buschdorf Jan Paul, Chong Yap Seng, Kwek Kenneth, Saw Seang Mei, Gluckman Peter D, Fortier Marielle V, Rifkin-Graboi Anne, Kobor Michael S, Qiu Anqi, Meaney Michael J, Holbrook Joanna D
Singapore Institute for Clinical Sciences.
National University of Singapore.
Dev Psychopathol. 2015 Feb;27(1):137-50. doi: 10.1017/S0954579414001357.
Early life environments interact with genotype to determine stable phenotypic outcomes. Here we examined the influence of a variant in the brain-derived neurotropic factor (BDNF) gene (Val66Met), which underlies synaptic plasticity throughout the central nervous system, on the degree to which antenatal maternal anxiety associated with neonatal DNA methylation. We also examined the association between neonatal DNA methylation and brain substructure volume, as a function of BDNF genotype. Infant, but not maternal, BDNF genotype dramatically influences the association of antenatal anxiety on the epigenome at birth as well as that between the epigenome and neonatal brain structure. There was a greater impact of antenatal maternal anxiety on the DNA methylation of infants with the methionine (Met)/Met compared to both Met/valine (Val) and Val/Val genotypes. There were significantly more cytosine-phosphate-guanine sites where methylation levels covaried with right amygdala volume among Met/Met compared with both Met/Val and Val/Val carriers. In contrast, more cytosine-phosphate-guanine sites covaried with left hippocampus volume in Val/Val infants compared with infants of the Met/Val or Met/Met genotype. Thus, antenatal Maternal Anxiety × BDNF Val66Met Polymorphism interactions at the level of the epigenome are reflected differently in the structure of the amygdala and the hippocampus. These findings suggest that BDNF genotype regulates the sensitivity of the methylome to early environment and that differential susceptibility to specific environmental conditions may be both tissue and function specific.
早期生活环境与基因型相互作用，以确定稳定的表型结果。在此，我们研究了脑源性神经营养因子（BDNF）基因（Val66Met）中的一个变体对产前母亲焦虑与新生儿DNA甲基化程度的影响，该变体是整个中枢神经系统突触可塑性的基础。我们还研究了新生儿DNA甲基化与脑亚结构体积之间的关联，作为BDNF基因型的函数。婴儿而非母亲的BDNF基因型显著影响出生时产前焦虑与表观基因组的关联，以及表观基因组与新生儿脑结构之间的关联。与甲硫氨酸（Met）/缬氨酸（Val）和Val/Val基因型相比，产前母亲焦虑对Met/Met基因型婴儿的DNA甲基化影响更大。与Met/Val和Val/Val携带者相比，Met/Met基因型中甲基化水平与右侧杏仁核体积共变的胞嘧啶-磷酸-鸟嘌呤位点明显更多。相比之下，与Met/Val或Met/Met基因型婴儿相比，Val/Val基因型婴儿中更多的胞嘧啶-磷酸-鸟嘌呤位点与左侧海马体体积共变。因此，产前母亲焦虑×BDNF Val66Met多态性在表观基因组水平上的相互作用在杏仁核和海马体结构中的反映有所不同。这些发现表明，BDNF基因型调节甲基化组对早期环境的敏感性，并且对特定环境条件的差异易感性可能具有组织和功能特异性。
