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

Ellen Verhoef,Chin Yang Shapland,Beate St Pourcain,Ditte Demontis,Jakob Grove,Stephen Burgess,Anders D Børglum,Dheeraj Rai

doi:10.1038/s41467-021-26755-1

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.

Highlights

The “*” symbol indicates the estimation of a polygenic risk effect with EA, here (^θ*ADHD), using alleles that were selected to increase liability for ASD, but are shared by position, here with ADHD risk
Using a multivariate analysis approach, we investigated genetic mechanisms embedded in ASD and ADHD genetic architectures that present as discordant polygenic association pattern with EA
We found strong evidence that EA-related genetic variation is shared across ASD and ADHD architectures, consistent with biological pleiotropy or high-LD co-localisation of genetic effects at the same subthreshold ASD- or ADHD-risk associated marker alleles

Summary

Introduction

Our findings, validated by the use of different GWAS summary statistics, suggest that discordant, and independent, genetic association patterns with EA are encoded across identical GWAS marker alleles that carry either subthreshold ASD or ADHD risk. Analysing ASD(iPSYCH,woADHD) and ADHD(iPSYCH) statistics, we identified evidence for shared genetic effects assuming a model of biological pleiotropy/high-LD co-localisation at three independent genomic regions (posterior probability > 0.9, Supplementary Fig. 3a).

Results

Conclusion