Background and Hypothesis 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. Study Designs 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. Study Results 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. Conclusions 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.

中文翻译：

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基因组-转录组-功能连接-认知联系区分精神分裂症和双相情感障碍

背景和假设 精神分裂症 (SZ) 和双相情感障碍 (BD) 具有共同的遗传危险因素，但患者表现出不同程度的认知障碍。我们假设基因组-转录组-功能连接（额顶叶）-认知通路与 SZ 与 BD 差异相关，并进行了一项多尺度研究来描述该通路。研究设计 大型全基因组研究提供了单核苷酸多态性 (SNP)，这些单核苷酸多态性 (SNP) 比 BD 赋予 SZ 更大的风险，并且我们确定了它们的调节基因，即偏向 SZ 的 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)，并检查了其与基于成像的额顶功能连接 (FC) 和认知表现的关联；(b) 检查了 SZ 偏向基因的离体死后表达与跨额顶叶区域的体内 SZ 相关 FC 破坏之间的空间相关性；(c) 研究了 SZ 与 BD 在额顶叶 FC 中的差异；(d) 评估额顶叶 FC 与认知表现的关联。研究结果 SZ 偏向 SNP 的 PRSSZ 与额顶叶 FC 和工作记忆测试分数显着相关。SZ 偏向基因的表达与额顶叶区域 FC 中 SZ 与 BD 的差异显着相关。与对照组相比，SZ 患者的额顶叶 FC 比 BD 患者减少更多。额顶叶 FC 与包括工作记忆在内的多个认知领域的测试分数以及所有认知领域的综合分数显着相关。结论 总的来说，这些多尺度研究结果支持这样的假设：SZ 偏向的遗传风险通过转录组调节与额顶叶连接障碍相关，这反过来又导致 SZ 与 BD 的认知缺陷差异，这表明潜在的生物标志物可以更精确地对患者进行分层和分类。治疗。