HTR1A 和 BDNF 风险基因的上位性改变皮质 5-HT1A 受体结合：PET 结果将基因型与抑郁症的分子表型联系起来。

Epistasis of HTR1A and BDNF risk genes alters cortical 5-HT1A receptor binding: PET results link genotype to molecular phenotype in depression.

机构信息

Department of Psychiatry and Psychotherapy, Medical University of Vienna, Wien, Austria.

Division of Nuclear Medicine, Department of Biomedical Imaging and Image-guided Therapy, Medical University of Vienna, Wien, Austria.

出版信息

Transl Psychiatry. 2019 Jan 16;9(1):5. doi: 10.1038/s41398-018-0308-2.

DOI:10.1038/s41398-018-0308-2

PMID:30664620

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6341100/

Abstract

Alterations of the 5-HT receptor and BDNF have consistently been associated with affective disorders. Two functional single nucleotide polymorphisms (SNPs), rs6295 of the serotonin 1A receptor gene (HTR1A) and rs6265 of brain-derived neurotrophic factor gene (BDNF), may impact transcriptional regulation and expression of the 5-HT receptor. Here we investigated interaction effects of rs6295 and rs6265 on 5-HT receptor binding. Forty-six healthy subjects were scanned with PET using the radioligand [carbonyl-C]WAY-100635. Genotyping was performed for rs6265 and rs6295. Subjects showing a genotype with at least three risk alleles (G of rs6295 or A of rs6265) were compared to control genotypes. Cortical surface binding potential (BP) was computed for 32 cortical regions of interest (ROI). Mixed model was applied to study main and interaction effects of ROI and genotype. ANOVA was used for post hoc analyses. Individuals with the risk genotypes exhibited an increase in 5-HT receptor binding by an average of 17% (mean BP 3.56 ± 0.74 vs. 2.96 ± 0.88). Mixed model produced an interaction effect of ROI and genotype on BP and differences could be demonstrated in 10 ROI post hoc. The combination of disadvantageous allelic expression of rs6295 and rs6265 may result in a 5-HT receptor profile comparable to affective disorders as increased 5-HT receptor binding is a well published phenotype of depression. Thus, epistasis between BDNF and HTR1A may contribute to the multifactorial risk for affective disorders and our results strongly advocate further research on this genetic signature in affective disorders.

摘要

5-羟色胺受体和脑源性神经营养因子的改变与情感障碍一直有关。两个功能性的单核苷酸多态性（SNP），即 5-羟色胺 1A 受体基因（HTR1A）的 rs6295 和脑源性神经营养因子基因（BDNF）的 rs6265，可能影响 5-羟色胺受体的转录调节和表达。在这里，我们研究了 rs6295 和 rs6265 对 5-羟色胺受体结合的相互作用效应。46 名健康受试者使用放射性配体 [羰基-C]WAY-100635 进行 PET 扫描。对 rs6265 和 rs6295 进行基因分型。与对照基因型相比，显示至少有三个风险等位基因（rs6295 的 G 或 rs6265 的 A）的基因型的受试者。计算了 32 个皮质感兴趣区（ROI）的皮质表面结合潜力（BP）。应用混合模型研究 ROI 和基因型的主效应和相互作用效应。方差分析用于事后分析。具有风险基因型的个体表现出 5-羟色胺受体结合增加了 17%（平均 BP 3.56±0.74 与 2.96±0.88）。混合模型产生了 ROI 和基因型对 BP 的相互作用效应，并且在 10 个 ROI 后可以证明差异。rs6295 和 rs6265 不利等位基因表达的组合可能导致 5-羟色胺受体谱类似于情感障碍，因为增加的 5-羟色胺受体结合是抑郁的一个很好的发表表型。因此，BDNF 和 HTR1A 之间的上位性可能有助于情感障碍的多因素风险，我们的结果强烈主张在情感障碍中进一步研究这种遗传特征。