Program in Genetics and Genome Biology and The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, Ontario, Canada.
Department of Statistics, University of Oxford, Oxford, UK.
Nat Med. 2020 Dec;26(12):1912-1918. doi: 10.1038/s41591-020-1103-1. Epub 2020 Nov 9.
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）与精神分裂症的 20-25%风险相关。在一个由 962 名 22q11DS 个体组成的队列中，我们研究了精神分裂症和与精神分裂症相关的早期轨迹表型（精神病阈下症状、低基线智力和认知下降）之间的共同遗传基础。我们研究了这些表型与两个多基因评分的关联，这些评分是为精神分裂症和智力而得出的，并评估了它们在 22q11DS 中的个体风险预测中的应用。多基因评分不仅与精神分裂症和基线智商（IQ）分别相关，而且精神分裂症多基因评分还与认知（言语 IQ）下降显著相关，与精神病阈下症状也有显著的关联。此外，在比较精神分裂症和 IQ 多基因评分分布的尾部十分位数时，22q11DS 中有 33%的个体患有精神分裂症，而有 9%的个体患有智力残疾；63%的个体患有智力残疾，而有 24%的个体患有智力残疾。总的来说，这些数据表明精神分裂症和与精神分裂症相关的表型具有共同的遗传基础，也突出了多基因评分在具有高度但不完全外显遗传变异的个体中进行风险分层的未来潜力。
