Neurodevelopmental abnormalities in neural connectivity have been long implicated in the etiology of schizophrenia (SCZ); however, it remains unclear whether these neural connectivity patterns are associated with genetic risk for SCZ in unaffected individuals (i.e., an absence of clinical features of SCZ or a family history of SCZ). We examine whether polygenic risk scores (PRS) for SCZ are associated with functional neural connectivity in adolescents and young adults without SCZ, whether this association is moderated by sex and age, and if similar associations are observed for genetically related neuropsychiatric PRS. One-thousand four-hundred twenty-six offspring from 913 families, unaffected with SCZ, were drawn from the Collaborative Study of the Genetics of Alcoholism (COGA) prospective cohort (median age at first interview = 15.6 (12–26), 51.6% female, 98.1% European American, 41% with a family history of alcohol dependence). Participants were followed longitudinally with resting-state EEG connectivity (i.e., coherence) assessed every two years. Higher SCZ PRS were associated with elevated theta (3–7 Hz) and alpha (7–12 Hz) EEG coherence. Associations differed by sex and age; the most robust associations were observed between PRS and parietal-occipital, central-parietal, and frontal-parietal alpha coherence among males between ages 15–19 (B: 0.15–0.21, p < 10^–4). Significant associations among EEG coherence and Bipolar and Depression PRS were observed, but differed from SCZ PRS in terms of sex, age, and topography. Findings reveal that polygenic risk for SCZ is robustly associated with increased functional neural connectivity among young adults without a SCZ diagnosis. Striking differences were observed between men and women throughout development, mapping onto key periods of risk for the onset of psychotic illness and underlining the critical importance of examining sex differences in associations with neuropsychiatric PRS across development.

长期以来，神经连接的神经发育异常与精神分裂症（SCZ）的病因有关。然而，尚不清楚这些神经连通性模式是否与未患病个体的SCZ遗传风险相关（即，没有SCZ的临床特征或SCZ的家族史）。我们检查了SCZ的多基因风险评分（PRS）是否与未患有SCZ的青少年和年轻人的功能性神经连通性相关，该关联是否由性别和年龄调节，以及是否在遗传相关的神经精神病PRS中观察到类似的关联。酒精中毒遗传学合作研究（COGA）前瞻性队列研究（来自首次酒精中毒年龄= 15.6（12-26），51），来自913个未受SCZ影响的家庭的146个后代。6％的女性，98.1％的亚裔美国人，41％的家族有酒精依赖史。每两年对参与者进行纵向随访，评估其静息状态的脑电图连通性（即一致性）。较高的SCZ PRS与theta（3–7 Hz）和alpha（7–12 Hz）脑电相干性升高相关。协会因性别和年龄而异；在15至19岁的男性中，PRS与顶枕，中央顶和额顶α相干性之间的关系最为紧密（B：0.15-0.21，p  < ^10-4）。观察到脑电图相关性与双相和抑郁PRS之间存在显着关联，但在性别，年龄和地形方面与SCZ PRS不同。研究结果表明，SCZ的多基因风险与未经SCZ诊断的年轻成年人的功能神经连通性增强密切相关。在整个发展过程中，观察到了男女之间的惊人差异，映射了精神病发作的关键风险时期，并强调了在整个发展过程中检查性别差异与神经精神病学PRS关联的至关重要性。