Shared polygenetic variation between ASD and ADHD exerts opposite association patterns with educational attainment

Autism Spectrum Disorder (ASD) and Attention-Deficit/Hyperactivity Disorder (ADHD) are genetically complex neurodevelopmental disorders that often co-occur. Besides some shared genetic aetiology, both conditions display apparent differences in their genetic architectures, especially in their genetic overlap with educational attainment (EA). Here, we investigate ASD-specific, ADHD-specific and cross-disorder genetic associations with EA using a multivariable regression (MVR) framework and genome-wide association summary statistics from large consortia. Our findings show that EA-related polygenic variation is shared across ASD and ADHD, irrespective of opposite association profiles. For example, ASD risk-increasing alleles selected at threshold P thr SNPs =1973), showed a 0.009 increase (SE=0.003) in years of education per log-odds ASD liability. Conditional on these effects, the same alleles captured a 0.029 decrease (SE=0.004) in years of education per log-odds ADHD liability. Likewise, ADHD risk-increasing alleles ( P thr SNPs =2717), showed an inverse ADHD-specific association with EA (β=-0.012(SE=0.003)), conditional on positive cross-disorder effects shared with ASD (β=0.022(SE=0.003)). MVR effect sizes increased when variants were restricted to markers tagging both ASD and ADHD, which at P thr SNPs =83) implicated many regulatory loci. The discovered inverse ADHD/ASD cross-disorder effects on EA were stronger and larger than for other combinations of psychiatric disorders, but are unlikely to be limited to ASD and ADHD. Thus, shared polygenic ASD/ADHD variation can, involving different combinations of the same risk-increasing alleles, reveal an opposite association profile with EA. These patterns are consistent with inverse EA-related genetic correlations between ASD and ADHD, as supported by simulations, and may affect the detectable net genetic overlap in cross-disorder investigations.