Tri-Institutional Center for Translational Research in Neuroimaging and Data Science (TReNDS), Georgia State University, Georgia Institute of Technology, and Emory University, Atlanta, GA, USA.
Department of Neurosciences, University of New Mexico School of Medicine, Albuquerque, NM, USA.
Schizophr Bull. 2022 Nov 18;48(6):1306-1317. doi: 10.1093/schbul/sbac088.
Schizophrenia (SZ) and bipolar disorder (BD) share genetic risk factors, yet patients display differential levels of cognitive impairment. We hypothesized a genome-transcriptome-functional connectivity (frontoparietal)-cognition pathway linked to SZ-versus-BD differences, and conducted a multiscale study to delineate this pathway.
Large genome-wide studies provided single nucleotide polymorphisms (SNPs) conferring more risk for SZ than BD, and we identified their regulated genes, namely SZ-biased SNPs and genes. We then (a) computed the polygenic risk score for SZ (PRSSZ) of SZ-biased SNPs and examined its associations with imaging-based frontoparietal functional connectivity (FC) and cognitive performances; (b) examined the spatial correlation between ex vivo postmortem expressions of SZ-biased genes and in vivo, SZ-related FC disruptions across frontoparietal regions; (c) investigated SZ-versus-BD differences in frontoparietal FC; and (d) assessed the associations of frontoparietal FC with cognitive performances.
PRSSZ of SZ-biased SNPs was significantly associated with frontoparietal FC and working memory test scores. SZ-biased genes' expressions significantly correlated with SZ-versus-BD differences in FC across frontoparietal regions. SZ patients showed more reductions in frontoparietal FC than BD patients compared to controls. Frontoparietal FC was significantly associated with test scores of multiple cognitive domains including working memory, and with the composite scores of all cognitive domains.
Collectively, these multiscale findings support the hypothesis that SZ-biased genetic risk, through transcriptome regulation, is linked to frontoparietal dysconnectivity, which in turn contributes to differential cognitive deficits in SZ-versus BD, suggesting that potential biomarkers for more precise patient stratification and treatment.
精神分裂症（SZ）和双相情感障碍（BD）共享遗传风险因素，但患者表现出不同程度的认知障碍。我们假设了一个与 SZ-与-BD 差异相关的基因组-转录组-功能连接（额顶叶）-认知途径，并进行了多尺度研究来描绘这条途径。
大规模全基因组研究提供了单核苷酸多态性（SNP），这些 SNP 赋予 SZ 比 BD 更高的风险，我们确定了它们的调节基因，即 SZ 偏向 SNP 和基因。然后，我们（a）计算了 SZ 偏向 SNP 的 SZ 多基因风险评分（PRSSZ），并研究了其与基于成像的额顶叶功能连接（FC）和认知表现的关联；（b）研究了 SZ 偏向基因的体外死后表达与体内 SZ 相关 FC 破坏之间的空间相关性，跨越额顶叶区域；（c）研究了额顶叶 FC 中的 SZ-与-BD 差异；（d）评估了额顶叶 FC 与认知表现的关联。
SZ 偏向 SNP 的 PRSSZ 与额顶叶 FC 和工作记忆测试分数显著相关。SZ 偏向基因的表达与额顶叶区域之间的 FC 的 SZ-与-BD 差异显著相关。与对照组相比，SZ 患者的额顶叶 FC 减少更为明显，而 BD 患者则较少。额顶叶 FC 与多个认知领域的测试分数显著相关，包括工作记忆，以及所有认知领域的综合分数。
综上所述，这些多尺度研究结果支持了以下假设：通过转录组调控，SZ 偏向的遗传风险与额顶叶功能连接不良有关，而额顶叶功能连接不良又导致 SZ 与 BD 之间的认知缺陷不同，这表明潜在的生物标志物可用于更精确的患者分层和治疗。
