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Genetic correlates of phenotypic heterogeneity in autism

Authors: Varun Warrier; Xinhe Zhang; Patrick Reed; Alexandra Havdahl; Tyler M. Moore; Freddy Cliquet; Claire S. Leblond; +76 Authors

Genetic correlates of phenotypic heterogeneity in autism

Abstract

AbstractThe substantial phenotypic heterogeneity in autism limits our understanding of its genetic aetiology. To address this gap, we investigated genetic differences between autistic individuals (Nmax= 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 butde novovariants were not, even though the latent factor structure was similar between carriers and non-carriers ofde novovariants. 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.

Countries
Norway, Denmark, France, Denmark, United Kingdom, Norway
Keywords

RISK, Male, ARCHITECTURE, IDENTIFICATION, Autism Spectrum Disorder, [SCCO.NEUR] Cognitive science/Neuroscience, 150, 610, CHILDREN, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, Article, AGE, Cognition, DE-NOVO MUTATIONS, Intellectual Disability, Humans, Female, GENOME-WIDE ASSOCIATION, SIMONS SIMPLEX COLLECTION, Autistic Disorder, COMMON, SPECTRUM DISORDER

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    popularity
    This indicator reflects the "current" impact/attention (the "hype") of an article in the research community at large, based on the underlying citation network.
    Top 1%
    influence
    This indicator reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).
    Top 10%
    impulse
    This indicator reflects the initial momentum of an article directly after its publication, based on the underlying citation network.
    Top 1%
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citations
This is an alternative to the "Influence" indicator, which also reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).
BIP!Citations provided by BIP!
popularity
This indicator reflects the "current" impact/attention (the "hype") of an article in the research community at large, based on the underlying citation network.
BIP!Popularity provided by BIP!
influence
This indicator reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).
BIP!Influence provided by BIP!
impulse
This indicator reflects the initial momentum of an article directly after its publication, based on the underlying citation network.
BIP!Impulse provided by BIP!
95
Top 1%
Top 10%
Top 1%
Green
hybrid