The substantial phenotypic heterogeneity in autism limits our understanding of its genetic aetiology. To address this gap, we investigated genetic differences between autistic individuals (N_max = 12,893) based on core (i.e., social communication difficulties, and restricted and repetitive behaviours) and associated features of autism, co-occurring developmental disabilities (e.g. language, motor, and intellectual developmental disabilities and delays), and sex. We conducted a comprehensive factor analysis of core autism features in autistic individuals and identified six factors. Common genetic variants including autism polygenic scores (PGS) were associated with the core factors but de novo variants were not, even though the latent factor structure was similar between carriers and non-carriers of de novo variants. We identify that increasing autism PGS decrease the likelihood of co- occurring developmental disabilities in autistic individuals, which reflects both a true protective effect and additivity between rare and common variants. Furthermore in autistic individuals without co-occurring intellectual disability (ID), autism PGS are overinherited by autistic females compared to males. Finally, we observe higher SNP heritability for males and autistic individuals without ID, but found no robust differences in SNP heritability by the level of core autism features. Deeper phenotypic characterisation will be critical to determining how the complex underlying genetics shapes cognition, behaviour, and co- occurring conditions in autism.

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自闭症表型异质性的遗传相关性

自闭症的大量表型异质性限制了我们对其遗传病因的理解。为了解决这个间隙中，我们调查自闭症个体之间（N遗传差异_最大= 12893）的基础上芯（即，社会交往困难和限制，并且重复行为）和相关的孤独症的特征，同现发育障碍（例如语言，马达，以及智力发育障碍和延迟），以及性别。我们对自闭症患者的核心自闭症特征进行了综合因素分析，并确定了六个因素。包括自闭症多基因评分 (PGS) 在内的常见遗传变异与核心因素相关，但从头开始变体不是，即使从头携带者和非携带者之间的潜在因子结构相似变种。我们发现增加自闭症 PGS 会降低自闭症个体共同发生发育障碍的可能性，这反映了罕见和常见变异之间的真正保护作用和可加性。此外，在没有共同发生智力障碍 (ID) 的自闭症个体中，与男性相比，自闭症女性过度遗传了自闭症 PGS。最后，我们观察到没有 ID 的男性和自闭症个体具有更高的 SNP 遗传力，但没有发现核心自闭症特征水平的 SNP 遗传力存在显着差异。更深层次的表型表征对于确定复杂的潜在遗传学如何塑造自闭症的认知、行为和共同发生的条件至关重要。