While the recurrent 22q11.2 deletion is one of the strongest genetic risk factors for schizophrenia (SCZ), variability of its associated neuropsychiatric endophenotypes reflects its incomplete penetrance for psychosis development. To assess whether this phenotypic variability is linked to common variants associated with SCZ, we studied the association between SCZ polygenic risk score (PRS) and longitudinally acquired phenotypic information of the Swiss 22q11.2DS cohort (n = 97, 50% females, mean age 17.7 yr, mean visit interval 3.8 yr). The SCZ PRS with the best predictive performance was ascertained in the Estonian Biobank (n = 201,146) with LDpred. The infinitesimal SCZ PRS model showed the strongest capacity in discriminating SCZ cases from controls with one SD difference in SCZ PRS corresponding to an odds ratio (OR) of 1.73 (95% CI 1.57–1.90, P = 1.47 × 10⁻²⁹). In 22q11.2 patients, random-effects ordinal regression modelling using longitudinal data showed SCZ PRS to have the strongest effect on social anhedonia (OR = 2.09, P = 0.0002), and occupational functioning (OR = 1.82, P = 0.0003) within the negative symptoms course, and dysphoric mood (OR = 2.00, P = 0.002) and stress intolerance (OR = 1.76, P = 0.0002) within the general symptoms course. Genetic liability for SCZ was additionally associated with full scale cognitive decline (β = –0.25, P = 0.02) and with longitudinal volumetric reduction of the right and left hippocampi (β = –0.28, P = 0.005; β = –0.23, P = 0.02, respectively). Our results indicate that the polygenic contribution to SCZ acts upon the threshold-lowering first hit (i.e., the deletion). It modifies the endophenotypes of 22q11.2DS and augments the derailment of developmental trajectories of negative and general symptoms, cognition, and hippocampal volume.

虽然反复出现的 22q11.2 缺失是精神分裂症 (SCZ) 最强的遗传风险因素之一，但其相关神经精神内表型的变异性反映了其对精神病发展的不完全外显率。为了评估这种表型变异性是否与 SCZ 相关的常见变异有关，我们研究了 SCZ 多基因风险评分 (PRS) 与瑞士 22q11.2DS 队列纵向获得的表型信息之间的关联（n = 97，50% 为女性，平均 年龄17.7 岁，平均就诊间隔 3.8 年）。在爱沙尼亚生物库中确定了具有最佳预测性能的 SCZ PRS ( n = 201,146) 与 LDpred。无穷小 SCZ PRS 模型显示出将 SCZ 病例与对照区分开来的最强能力，SCZ PRS 中的一个 SD 差异对应于 1.73 的优势比 (OR)（95% CI 1.57–1.90，P = 1.47 × 10  -29 ^）。在 22q11.2 患者中，使用纵向数据的随机效应有序回归模型显示 SCZ PRS 对社交快感缺乏（OR = 2.09，P  = 0.0002）和职业功能（OR = 1.82，P  = 0.0003）的影响最强阴性症状病程、烦躁情绪（OR = 2.00，P  = 0.002）和压力不耐受（OR = 1.76，P = 0.0002) 在一般症状过程中。SCZ 的遗传责任还与全面认知能力下降（β = –0.25，P  = 0.02）和左右海马体的纵向体积减少（β = –0.28，P  = 0.005；β = –0.23，P  = 0.02，分别）。我们的结果表明，对 SCZ 的多基因贡献作用于降低阈值的首次命中（即删除）。它修改了 22q11.2DS 的内表型，并增加了负面和一般症状、认知和海马体积的发育轨迹的脱轨。