Abstract
BackgroundRecent analyses of trait-disorder overlap suggest that psychiatric dimensions may relate to distinct sets of genes that exert maximum influence during different periods of development. This includes analyses of social communication difficulties that share, depending on their developmental stage, stronger genetic links with either autism spectrum disorder or schizophrenia. We developed a multivariate analysis framework in unrelated individuals to model directly the developmental profile of genetic influences contributing to complex traits, such as social communication difficulties, during an approximately 10-year period spanning childhood and adolescence. MethodsLongitudinally assessed quantitative social communication problems (N ≤ 5551) were studied in participants from a United Kingdom birth cohort (Avon Longitudinal Study of Parents and Children; age range, 8–17 years). Using standardized measures, genetic architectures were investigated with novel multivariate genetic-relationship-matrix structural equation models incorporating whole-genome genotyping information. Analogous to twin research, genetic-relationship-matrix structural equation models included Cholesky decomposition, common pathway, and independent pathway models. ResultsA two-factor Cholesky decomposition model described the data best. One genetic factor was common to Social Communication Disorder Checklist measures across development; the other accounted for independent variation at 11 years and later, consistent with distinct developmental profiles in trait-disorder overlap. Importantly, genetic factors operating at 8 years explained only approximately 50% of genetic variation at 17 years. ConclusionsUsing latent factor models, we identified developmental changes in the genetic architecture of social communication difficulties that enhance the understanding of autism spectrum disorder– and schizophrenia-related dimensions. More generally, genetic-relationship-matrix structural equation models present a framework for modeling shared genetic etiologies between phenotypes and can provide prior information with respect to patterns and continuity of trait-disorder overlap.
Highlights
Recent analyses of trait-disorder overlap suggest that psychiatric dimensions may relate to distinct sets of genes that exert maximum influence during different periods of development
Building on our previous work [2,9], we investigate here two extreme hypotheses, as follows: 1) whether the genetic variance/covariance structure of social communication difficulties during childhood and adolescence is consistent with multiple independent genetic influences, suggesting developmental changes in the genes responsible for interindividual variation over time, or 2) whether, alternatively, there is evidence for a shared single genetic factor, irrespective of age
Using a structural equation modeling (SEM) framework [17], as widely applied within twin research [4,5], we extend this bivariate approach by flexibly modeling complex latent genetic factor structures within a multivariate context
Summary
Recent analyses of trait-disorder overlap suggest that psychiatric dimensions may relate to distinct sets of genes that exert maximum influence during different periods of development. This includes analyses of social communication difficulties that share, depending on their developmental stage, stronger genetic links with either autism spectrum disorder or schizophrenia. We developed a multivariate analysis framework in unrelated individuals to model directly the developmental profile of genetic influences contributing to complex traits, such as social communication difficulties, during an approximately 10-year period spanning childhood and adolescence. One genetic factor was common to Social Communication Disorder Checklist measures across development; the other accounted for independent variation at 11 years and later, consistent with distinct developmental profiles in trait-disorder overlap. Genetic-relationship-matrix structural equation models present a framework for modeling shared genetic etiologies between phenotypes and can provide prior information with respect to patterns and continuity of trait-disorder overlap
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