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Common genetic variation has been associated with multiple phenotypic features in Autism Spectrum Disorder (ASD). However, our knowledge of shared genetic factor structures contributing to this highly heterogeneous phenotypic spectrum is limited. Here, we developed and implemented a structural equation modelling framework to directly model genomic covariance across core and non-core ASD phenotypes, studying autistic individuals of European descent with a case-only design. We identified three independent genetic factors most strongly linked to language performance, behaviour and developmental motor delay, respectively, studying an autism community sample (N = 5331). The three-factorial structure was largely confirmed in independent ASD-simplex families (N = 1946), although we uncovered, in addition, simplex-specific genetic overlap between behaviour and language phenotypes. Multivariate models across cohorts revealed novel associations, including links between language and early mastering of self-feeding. Thus, the common genetic architecture in ASD is multi-dimensional with overarching genetic factors contributing, in combination with ascertainment-specific patterns, to phenotypic heterogeneity. Studying individuals with autism only, this study investigated the genomic architecture of autism-related phenotypes using a multivariate modelling framework. This work identified distinct genomic factors linked to language performance, behaviour and developmental motor delay. [ABSTRACT FROM AUTHOR]

Pairwise maximum likelihood (PML) estimation is a promising method for multilevel models with discrete responses. Multilevel models take into account that units within a cluster tend to be more alike than units from different clusters. The pairwise likelihood is then obtained as the product of bivariate likelihoods for all within‐cluster pairs of units and items. In this study, we investigate the PML estimation method with computationally intensive multilevel random intercept and random slope structural equation models (SEM) in discrete data. In pursuing this, we first reconsidered the general 'wide format' (WF) approach for SEM models and then extend the WF approach with random slopes. In a small simulation study we the determine accuracy and efficiency of the PML estimation method by varying the sample size (250, 500, 1000, 2000), response scales (two‐point, four‐point), and data‐generating model (mediation model with three random slopes, factor model with one and two random slopes). Overall, results show that the PML estimation method is capable of estimating computationally intensive random intercept and random slopes multilevel models in the SEM framework with discrete data and many (six or more) latent variables with satisfactory accuracy and efficiency. However, the condition with 250 clusters combined with a two‐point response scale shows more bias. [ABSTRACT FROM AUTHOR]