Transcriptome-based polygenic score links depression-related corticolimbic gene expression changes to sex-specific brain morphology and depression risk.
Transcriptome-based polygenic score links depression-related corticolimbic gene expression changes to sex-specific brain morphology and depression risk.
复制标题
基于转录组的多基因评分将抑郁相关的皮质边缘基因表达变化与性别特异性大脑形态和抑郁风险联系起来。
DOI：
10.1038/s41386-021-01189-x
复制
发表时间：
2021
期刊：
影响因子：
--
通讯作者：
Uher,Rudo
中科院分区：
文献类型：
--
作者：
Miles,AmyE;DosSantos,FernandaC;Byrne,EndaM;Renteria,MiguelE;McIntosh,AndrewM;Adams,MarkJ;Pistis,Giorgio;Castelao,Enrique;Preisig,Martin;Baune,BernhardT;Schubert,KOliver;Lewis,CathrynM;Jones,LisaA;Jones,Ian;Uher,Rudo
对死后人脑组织的研究表明，严重抑郁障碍(MDD)与皮质转录改变有关，其在体内的潜在影响仍未被探索。为了解决这一翻译差距，我们最近开发了一种基于转录组的多基因风险评分(T-PRS)，该评分基于常见的功能变体，捕捉皮质基因表达的“抑郁样”变化。在这里，我们使用了一个非临床的年轻人样本(n= 482，杜克大学神经遗传学研究：53%的女性；年龄19.8 ± 1.2岁)，将T-PR映射到脑形态测量上，包括自由下水派生的皮质下体积、皮质厚度、表面积、局部回转指数，以及广泛的MDD风险，以自我报告的抑郁症家族史为指标。我们进行了与来自精神病学基因组学联盟MDD GAS(PGC-PR)的独立PR的并列比较，并试图将T-PR与PGC-MDD参与者的诊断和症状严重程度直接联系起来(n= 29,340，59%女性；12,923例MDD病例，16,417名对照)。在女性中，T-PR与较小的杏仁核体积(t= −3.478，p= 0.001)和较低的性别前额叶回有关。在男性中，T-PRS与颞枕区的高回旋相关。前额叶低回在T-PR和家族性抑郁之间介导了男性特有的间接联系(b= 0.005，p= 0.029)。PGC-PR类似地与杏仁核体积降低和皮质回变相关；然而，这两种影响都是男性特有的，并且在不同的顶枕区出现回缩不足，与家族性抑郁症无关。在妊娠期胃肠道疾病中，T-PR不能预测诊断(OR = 1.007，95%CI = [0.997-1.018])，但与一个队列中男性的症状严重程度(Rho = 0.175，p= 7.957 × 10−4)相关(N= 762，48%男性)。皮质基因表达的抑郁症样变化对大脑形态有性别特异性的影响，并可能导致男性普遍的抑郁症易感性。
Studies in post-mortem human brain tissue have associated major depressive disorder (MDD) with cortical transcriptomic changes, whose potential in vivo impact remains unexplored. To address this translational gap, we recently developed a transcriptome-based polygenic risk score (T-PRS) based on common functional variants capturing ‘depression-like’ shifts in cortical gene expression. Here, we used a non-clinical sample of young adults (n= 482, Duke Neurogenetics Study: 53% women; aged 19.8 ± 1.2 years) to map T-PRS onto brain morphology measures, including Freesurfer-derived subcortical volume, cortical thickness, surface area, and local gyrification index, as well as broad MDD risk, indexed by self-reported family history of depression. We conducted side-by-side comparisons with a PRS independently derived from a Psychiatric Genomics Consortium (PGC) MDD GWAS (PGC-PRS), and sought to link T-PRS with diagnosis and symptom severity directly in PGC-MDD participants (n= 29,340, 59% women; 12,923 MDD cases, 16,417 controls). T-PRS was associated with smaller amygdala volume in women (t= −3.478,p= 0.001) and lower prefrontal gyrification across sexes. In men, T-PRS was associated with hypergyrification in temporal and occipital regions. Prefrontal hypogyrification mediated a male-specific indirect link between T-PRS and familial depression (b= 0.005,p= 0.029). PGC-PRS was similarly associated with lower amygdala volume and cortical gyrification; however, both effects were male-specific and hypogyrification emerged in distinct parietal and temporo-occipital regions, unassociated with familial depression. In PGC-MDD, T-PRS did not predict diagnosis (OR = 1.007, 95% CI = [0.997–1.018]) but correlated with symptom severity in men (rho = 0.175,p= 7.957 × 10−4) in one cohort (N= 762, 48% men). Depression-like shifts in cortical gene expression have sex-specific effects on brain morphology and may contribute to broad depression vulnerability in men.