Multiplex families have higher recurrence risk of schizophrenia compared to the families of sporadic cases, but the source of this increased recurrence risk is unknown. We used schizophrenia genome-wide association study data (N=156,509) to construct polygenic risk scores (PRS) in 1,005 individuals from 257 multiplex schizophrenia families, 2,114 ancestry-matched sporadic cases, and 2,205 population controls, to evaluate whether increased PRS can explain the higher recurrence risk of schizophrenia in multiplex families compared to ancestry-matched sporadic cases. Using mixed-effects logistic regression with family structure modeled as a random effect, we show that SCZ PRS in familial cases does not differ significantly from sporadic cases either with, or without family history (FH) of psychotic disorders (All sporadic cases p = 0.92, FH+ cases p = 0.88, FH-cases p = 0.82). These results indicate that increased burden of common schizophrenia risk variation as indexed by current SCZ PRS, is unlikely to account for the higher recurrence risk of schizophrenia in multiplex families. In the absence of elevated PRS, segregation of rare risk variation or environmental influences unique to the families may explain the increased familial recurrence risk. These findings also further validate a genetically influenced psychosis spectrum, as shown by a continuous increase of common SCZ risk variation burden from unaffected relatives to schizophrenia cases in multiplex families. Finally, these results suggest that common risk variation loading are unlikely to be predictive of schizophrenia recurrence risk in the families of index probands, and additional components of genetic risk must be identified and included in order to improve recurrence risk prediction.

中文翻译：

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评估常见风险变异在多发性精神分裂症家族中精神分裂症复发风险中的作用

与散发病例的家庭相比，多重家庭的精神分裂症复发风险更高，但这种增加的复发风险的来源尚不清楚。我们使用精神分裂症全基因组关联研究数据 (N=156,509) 来构建来自 257 个多重精神分裂症家族、2,114 名血统匹配的散发病例和 2,205 名人群对照的 1,005 名个体的多基因风险评分 (PRS)，以评估 PRS 增加是否可以解释与血统匹配的散发病例相比，多重家庭中精神分裂症的复发风险更高。使用混合效应逻辑回归，将家庭结构建模为随机效应，我们表明家族病例中的 SCZ PRS 与有或没有精神病家族史 (FH) 的散发病例没有显着差异（所有散发病例p = 0.92，FH+ 病例p = 0.88，FH-病例p= 0.82)。这些结果表明，根据当前 SCZ PRS 指数，常见精神分裂症风险变异的负担增加，不太可能解释多重家庭中精神分裂症的较高复发风险。在没有升高的 PRS 的情况下，家庭特有的罕见风险变异或环境影响的隔离可以解释家庭复发风险增加。这些发现还进一步验证了受遗传影响的精神病谱，如从未受影响的亲属到多重家庭中的精神分裂症病例的常见 SCZ 风险变异负担持续增加所示。最后，这些结果表明，常见的风险变化负荷不太可能预测指数先证者家庭的精神分裂症复发风险，