Department of Quantitative Health Sciences, Cleveland Clinic, Cleveland, OH, USA.
Department of Psychiatry, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Transl Psychiatry. 2022 Apr 4;12(1):137. doi: 10.1038/s41398-022-01892-3.
We investigated gene-environment effects on structural brain endophenotype in bipolar disorder (BD) using a novel method of combining polygenic risk scores with epigenetic signatures since traditional methods of examining the family history and trauma effects have significant limitations. The study enrolled 119 subjects, including 55 BD spectrum (BDS) subjects diagnosed with BD or major depressive disorder (MDD) with subthreshold BD symptoms and 64 non-BDS subjects comprising 32 MDD subjects without BD symptoms and 32 healthy subjects. The blood samples underwent genome-wide genotyping and methylation quantification. We derived polygenic risk score (PRS) and methylation profile score (MPS) as weighted summations of risk single nucleotide polymorphisms and methylation probes, respectively, which were considered as molecular measures of genetic and environmental risks for BD. Linear regression was used to relate PRS, MPS, and their interaction to 44 brain structure measures quantified from magnetic resonance imaging (MRI) on 47 BDS subjects, and the results were compared with those based on family history and childhood trauma. After multiplicity corrections using false discovery rate (FDR), MPS was found to be negatively associated with the volume of the medial geniculate thalamus (FDR = 0.059, partial R = 0.208). Family history, trauma scale, and PRS were not associated with any brain measures. PRS and MPS show significant interactions on whole putamen (FDR = 0.09, partial R = 0.337). No significant gene-environment interactions were identified for the family history and trauma scale. PRS and MPS generally explained greater proportions of variances of the brain measures (range of partial R = [0.008, 0.337]) than the clinical risk factors (range = [0.004, 0.228]).
我们使用一种将多基因风险评分与表观遗传特征相结合的新方法研究双相障碍（BD）的结构性脑内表型的基因-环境效应，因为传统的检查家族史和创伤效应的方法存在显著的局限性。该研究纳入了 119 名受试者，包括 55 名双相谱系（BDS）受试者，他们被诊断为 BD 或伴有亚阈值 BD 症状的重度抑郁症（MDD），以及 64 名非 BDS 受试者，其中包括 32 名无 BD 症状的 MDD 受试者和 32 名健康受试者。血液样本进行了全基因组基因分型和甲基化定量分析。我们得出多基因风险评分（PRS）和甲基化谱评分（MPS），分别作为风险单核苷酸多态性和甲基化探针的加权总和，它们被认为是 BD 的遗传和环境风险的分子度量。线性回归用于将 PRS、MPS 及其相互作用与从 47 名 BDS 受试者的磁共振成像（MRI）量化的 44 个大脑结构测量值相关联，并将结果与基于家族史和儿童创伤的结果进行比较。使用错误发现率（FDR）进行多重校正后，发现 MPS 与内侧膝状体丘脑体积呈负相关（FDR=0.059，部分 R=0.208）。家族史、创伤量表和 PRS 与任何大脑测量值均无关联。PRS 和 MPS 对整个壳核表现出显著的相互作用（FDR=0.09，部分 R=0.337）。家族史和创伤量表未鉴定出显著的基因-环境相互作用。PRS 和 MPS 通常比临床危险因素（范围= [0.004，0.228]）解释更多的大脑测量值的方差比例（范围的部分 R= [0.008，0.337]）。
