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Discordant associations of educational attainment with ASD and ADHD implicate a polygenic form of pleiotropy

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  • Ellen Verhoef, Max Planck Institute for Psycholinguistics, International Max Planck Research School for Language Sciences
  • ,
  • Jakob Grove
  • Chin Yang Shapland, University of Bristol
  • ,
  • Ditte Demontis
  • Stephen Burgess, University of Cambridge
  • ,
  • Dheeraj Rai, University of Bristol, Avon and Wiltshire Mental Health Partnership NHS Trust
  • ,
  • Anders D. Børglum
  • Beate St Pourcain, Max Planck Institute for Psycholinguistics, Radboud University Nijmegen, University of Bristol

Autism Spectrum Disorder (ASD) and Attention-Deficit/Hyperactivity Disorder (ADHD) are complex co-occurring neurodevelopmental conditions. Their genetic architectures reveal striking similarities but also differences, including strong, discordant polygenic associations with educational attainment (EA). To study genetic mechanisms that present as ASD-related positive and ADHD-related negative genetic correlations with EA, we carry out multivariable regression analyses using genome-wide summary statistics (N = 10,610–766,345). Our results show that EA-related genetic variation is shared across ASD and ADHD architectures, involving identical marker alleles. However, the polygenic association profile with EA, across shared marker alleles, is discordant for ASD versus ADHD risk, indicating independent effects. At the single-variant level, our results suggest either biological pleiotropy or co-localisation of different risk variants, implicating MIR19A/19B microRNA mechanisms. At the polygenic level, they point to a polygenic form of pleiotropy that contributes to the detectable genome-wide correlation between ASD and ADHD and is consistent with effect cancellation across EA-related regions.

OriginalsprogEngelsk
Artikelnummer6534
TidsskriftNature Communications
Vol/bind12
ISSN2041-1723
DOI
StatusUdgivet - nov. 2021

Bibliografisk note

Funding Information:
This research was facilitated by the Social Science Genetic Association Consortium (SSGAC), Complex Trait Genetics (CTG) lab, Psychiatric Genomics Consortium (PGC) and iPSYCH-Broad-PGC ASD Consortium, by providing access to GWAS summary statistics. This publication is the work of the authors and E.V. and B.S.T.P. will serve as guarantors for the contents of this paper. E.V. and B.S.T.P. are supported by the Max Planck Society. B.S.T.P. is supported by the Simons Foundation (Award ID: 514787). The iPSYCH project is funded by the Lundbeck Foundation (grant no R102-A9118 and R155-2014-1724) and the universities and university hospitals of Aarhus and Copenhagen. A.D.B. is also supported by the EU’s Horizon 2020 programme (grant no 667302, CoCA). Data handling and analysis was supported by NIMH (1U01MH109514-01 to Michael O’Donovan and Anders D Børglum). High-performance computer capacity for handling and statistical analysis of iPSYCH data on the GenomeDK HPC facility was provided by the Centre for Integrative Sequencing, iSEQ, Aarhus University, Denmark (grant to Anders D Børglum) and Center for Genomics and Personalized Medicine, Aarhus, Denmark. D.R. is supported by the NHR Biomedical Research Centre at University Hospitals Bristol and Weston NHS Foundation Trust and the University of Bristol. We thank Simon E. Fisher for helpful discussions of the manuscript. The views in this paper are those of the authors and not the funders. A previous version of this manuscript is available as preprint: https://doi.org/10.1101/580365.

Publisher Copyright:
© 2021, The Author(s).

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