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University of Cambridge [UK] (CAM), Génétique humaine et fonctions cognitives - Human Genetics and Cognitive Functions (GHFC (UMR_3571 / U-Pasteur_1)), Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris]-Université de Paris (UP), V.W. is funded by St. Catharines College, Cambridge. This study was funded by grants to SBC from the Medical Research Council, the Wellcome Trust, the Autism Research Trust, the Templeton World Charity Foundation, and to T.B. from the Institut Pasteur, the CNRS, The Bettencourt-Schueller and the Cognacq-Jay Foundations, the APHP and the Universite de Paris. SBC was funded by the Autism Research Trust, the Wellcome Trust, the Templeton World Charitable Foundation, and the NIHR Biomedical Research Centre in Cambridge, during the period of this work., List of authors and their affiliations for the EU-AIMS LEAP group : KCL: Dr Antonia San Jose Caceres, Hannah Hayward, Daisy Crawley, Jessica Faulkner, Jessica Sabet, Claire Ellis, Bethany Oakley, Dr. Eva Loth, Prof. Tony Charman, Prof. Declan Murphy, University of Cambridge: Dr. Rosemary Holt , Jack Waldman, Jessica Upadhyay, Nicola Gunby, Dr. Meng-Chuan Lai, Gwilym Renouf, Dr. Amber Ruigrok, Emily Taylor, Dr. Hisham Ziauddeen, Dr. Julia Deakin, Professor Simon Baron-Cohen, UMC Utrecht: Sara Ambrosino di Bruttopilo, Sarai van Dijk, Yvonne Rijks, Tabitha Koops, Miriam Douma, Alyssia Spaan, Iris Selten, Maarten Steffers, Anna Ver Loren van Themaat, Central Institute of Mental Health Mannheim: Dr. Nico Bast, Dr. Sarah Baumeister, Radboudumc: Dr Larry O’Dwyer, Carsten Bours, Annika Rausch Dr. Daniel von Rhein, Ineke Cornelissen, Yvette de Bruin, Maartje Graauwmans, Karolinska Institutet: Elzbieta Kostrzewa, Elodie Cauvet, Dr. Kristiina Tammimies, Rouslan Sitnikow, Institut Pasteur: Dr. Guillaume Dumas, Dr. Yang-Min Kim, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité) |
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Posté sur medRxiv le 24 juillet 2020.; ImportanceSchizophrenia, educational attainment, and intelligence are all genetically correlated with autism. However, autism is a complex condition, with several different core (such as social communication difficulties and repetitive and restricted behaviour) and associated features (such as IQ and adaptive behaviour) contributing to the underlying heterogeneity. It is unknown to what extent polygenic scores (PGS) for these three phenotypes are associated with the core and associated autism features.ObjectiveTo investigate the association of PGS for intelligence, educational attainment and schizophrenia on core autism features, IQ and adaptive behaviour in autistic individuals. To further investigate the effects of stratifying by sex and IQ on these associations.DesignPGS association for the three phenotypes with 12 different autism core and associated features in three cohorts followed by meta-analysis. We additionally conducted sensitivity analyses by stratifying for sex and IQ.Settings :Three cross-sectional, multi-centre cohorts comprising autistic with genotype data, and phenotypic information.ParticipantsAutistic individuals (total N: 2,512 – 3,681) from three different cohorts: Simons Simplex Collection (Nmax = 2,233), Autism Genetic Research Exchange (Nmax = 1,200), and AIMS-2- TRIALS LEAP (Nmax = 262)Main outcome measuresAssociation of PGS for intelligence, educational attainment, and schizophrenia with core autism features, measures of intelligence, and adaptive behaviour in autistic individualsResultsWe identified a similar pattern of correlation among core and associated autism features across all three cohorts. Cluster analyses of these features identified two broad clusters – one consisting of the core features, and another consisting of IQ and adaptive behaviour. PGS for intelligence were only associated with measures of intelligence and adaptive behaviour (e.g. for full-scale IQ, Beta = 0.08, 95%CI = 0.11 – 0.04) for PGS for educational attainment were associated for measures of intelligence, adaptive behaviour, and additionally, non-verbal communication as measured by ADI – a core-autism feature (e.g. for full-scale IQ, Beta = 0.05, 95%CI = 0.08 – 0.02; for ADI non-verbal communication, Beta = 0.05, 95%CI = 0.09 – 0.01). Finally, PGS for schizophrenia were associated with two core autism features: restricted and repetitive behaviour and verbal communication difficulties as measured by the ADI-R (e.g. for ADI restricted and repetitive behaviour: Beta = 0.06, 95%CI = 0.09 – 0.02). Most of these associations were also significant when restricting it to males only or to individuals with IQ > 70. We find limited evidence for heterogeneity between cohorts.Conclusion and relevanceWe identify specific and different patterns of association between PGS for the three phenotypes and core and associated autism features. This provides greater resolution into the shared genetics between autism and the three phenotypes, and suggests one method to investigate heterogeneity in autism and co-occurring conditions. |
