Although rare neurodevelopmental conditions have a large Mendelian component¹, common genetic variants also contribute to risk^2,3. However, little is known about how this polygenic risk is distributed among patients with these conditions and their parents nor its interplay with rare variants. It is also unclear whether polygenic background affects risk directly through alleles transmitted from parents to children, or whether indirect genetic effects mediated through the family environment⁴ also play a role. Here we addressed these questions using genetic data from 11,573 patients with rare neurodevelopmental conditions, 9,128 of their parents and 26,869 controls. Common variants explained around 10% of variance in risk. Patients with a monogenic diagnosis had significantly less polygenic risk than those without, supporting a liability threshold model⁵. A polygenic score for neurodevelopmental conditions showed only a direct genetic effect. By contrast, polygenic scores for educational attainment and cognitive performance showed no direct genetic effect, but the non-transmitted alleles in the parents were correlated with the child’s risk, potentially due to indirect genetic effects and/or parental assortment for these traits⁴. Indeed, as expected under parental assortment, we show that common variant predisposition for neurodevelopmental conditions is correlated with the rare variant component of risk. These findings indicate that future studies should investigate the possible role and nature of indirect genetic effects on rare neurodevelopmental conditions, and consider the contribution of common and rare variants simultaneously when studying cognition-related phenotypes.

尽管罕见的神经发育疾病具有较大的孟德尔成分¹，但常见的遗传变异也会导致风险^2,3。然而，关于这种多基因风险在患有这些疾病的患者及其父母之间是如何分布的，以及它与罕见变异的相互作用，人们知之甚少。目前还不清楚多基因背景是否通过从父母传给孩子的等位基因直接影响风险，或者通过家庭环境⁴ 介导的间接遗传效应是否也起作用。在这里，我们使用来自 11,573 名罕见神经发育疾病患者、9,128 名父母和 26,869 名对照的遗传数据来回答这些问题。常见变异解释了大约 10% 的风险方差。单基因诊断的患者多基因风险明显低于未诊断的患者，支持责任阈值模型⁵。神经发育状况的多基因评分仅显示直接的遗传效应。相比之下，受教育程度和认知表现的多基因评分没有显示直接的遗传效应，但父母中的非传递等位基因与孩子的风险相关，这可能是由于间接遗传效应和/或这些特征的父母分类⁴。事实上，正如在父母分类下预期的那样，我们表明神经发育状况的常见变异易感性与风险的罕见变异成分相关。这些发现表明，未来的研究应调查间接遗传效应对罕见神经发育状况的可能作用和性质，并在研究认知相关表型时同时考虑常见和罕见变异的贡献。