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

Ellen Verhoef, Jakob Grove, Chin Yang Shapland, Ditte Demontis, Stephen Burgess, Dheeraj Rai, Anders D. Børglum and Beate St Pourcain ()
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Ellen Verhoef: Max Planck Institute for Psycholinguistics
Jakob Grove: The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH
Chin Yang Shapland: University of Bristol
Ditte Demontis: The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH
Stephen Burgess: University of Cambridge
Dheeraj Rai: University of Bristol
Anders D. Børglum: The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH
Beate St Pourcain: Max Planck Institute for Psycholinguistics

Nature Communications, 2021, vol. 12, issue 1, 1-14

Abstract: Abstract 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.

Date: 2021
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DOI: 10.1038/s41467-021-26755-1

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