The 22q11.2 deletion syndrome (22q11DS) is associated with a 20–25% risk of schizophrenia. In a cohort of 962 individuals with 22q11DS, we examined the shared genetic basis between schizophrenia and schizophrenia-related early trajectory phenotypes: sub-threshold symptoms of psychosis, low baseline intellectual functioning and cognitive decline. We studied the association of these phenotypes with two polygenic scores, derived for schizophrenia and intelligence, and evaluated their use for individual risk prediction in 22q11DS. Polygenic scores were not only associated with schizophrenia and baseline intelligence quotient (IQ), respectively, but schizophrenia polygenic score was also significantly associated with cognitive (verbal IQ) decline and nominally associated with sub-threshold psychosis. Furthermore, in comparing the tail-end deciles of the schizophrenia and IQ polygenic score distributions, 33% versus 9% of individuals with 22q11DS had schizophrenia, and 63% versus 24% of individuals had intellectual disability. Collectively, these data show a shared genetic basis for schizophrenia and schizophrenia-related phenotypes and also highlight the future potential of polygenic scores for risk stratification among individuals with highly, but incompletely, penetrant genetic variants.

22q11.2 缺失综合征 (22q11DS) 与 20-25% 的精神分裂症风险相关。在 962 名 22q11DS 个体的队列中，我们检查了精神分裂症和精神分裂症相关早期轨迹表型之间的共同遗传基础：精神病的阈下症状、低基线智力功能和认知能力下降。我们研究了这些表型与源自精神分裂症和智力的两个多基因评分的关联，并评估了它们在 22q11DS 个体风险预测中的应用。多基因评分不仅分别与精神分裂症和基线智商（IQ）相关，而且精神分裂症多基因评分还与认知（语言智商）下降显着相关，并且名义上与阈下精神病相关。此外，在比较精神分裂症和智商多基因得分分布的尾端十分位时，22q11DS 患者中分别有 33% 和 9% 的人患有精神分裂症，63% 和 24% 的人有智力障碍。总的来说，这些数据显示了精神分裂症和精神分裂症相关表型的共同遗传基础，并且还强调了多基因评分在具有高度但不完全渗透性遗传变异的个体中进行风险分层的未来潜力。