Disentangling polygenic associations between attention-deficit/hyperactivity disorder, educational attainment, literacy and language
Authors: Verhoef Ellen , Demontis Ditte , Burgess Stephen , Shapland Chin Yang , Dale Philip S. , Okbay Aysu , Neale Benjamin M. , Faraone Stephen V. ,   iPSYCH-Broad-PGC ADHD Consortium, Agerbo Esben , Als Thomas Damm , Bækved-Hansen Marie , Belliveau Rich , Børglum Anders D. , Bybjerg-Grauholm Jonas , Cerrato Felecia , Chambert Kimberly , Churchhouse Claire , Dalsgaard Søren , Daly Mark J. , Demontis Ditte , Dumont Ashley , Goldstein Jacqueline , Grove Jakob , Hansen Christine S. , Hauberg Mads Engel , Hollegaard Mads V. , Hougaard David M. , Howrigan Daniel P. , Huang Hailiang , Maller Julian , Martin Alicia R. , Martin Joanna , Mattheisen Manuel , Moran Jennifer , Mors Ole , Mortensen Preben Bo , Neale Benjamin M. , Nordentoft Merete , Pallesen Jonatan , Palmer Duncan S. , Pedersen Carsten Bøcker , Pedersen Marianne Giørtz , Poterba Timothy , Poulsen Jesper Buchhave , Ripke Stephan , Robinson Elise B. , Satterstrom F. Kyle , Stevens Christine , Turley Patrick , Walters Raymond K. , Werge Thomas , Stergiakouli Evie , Davey Smith George , Fisher Simon E. , Børglum Anders D. , St Pourcain Beate 
Published: January 2019

Interpreting polygenic overlap between ADHD and both literacy-related and language-related impairments is challenging as genetic associations might be influenced by indirectly shared genetic factors. Here, we investigate genetic overlap between polygenic ADHD risk and multiple literacy-related and/or language-related abilities (LRAs), as assessed in UK children (N ≤ 5919), accounting for genetically predictable educational attainment (EA). Genome-wide summary statistics on clinical ADHD and years of schooling were obtained from large consortia (N ≤ 326,041). Our findings show that ADHD-polygenic scores (ADHD-PGS) were inversely associated with LRAs in ALSPAC, most consistently with reading-related abilities, and explained ≤1.6% phenotypic variation. These polygenic links were then dissected into both ADHD effects shared with and independent of EA, using multivariable regressions (MVR). Conditional on EA, polygenic ADHD risk remained associated with multiple reading and/or spelling abilities, phonemic awareness and verbal intelligence, but not listening comprehension and non-word repetition. Using conservative ADHD-instruments (P-threshold < 5 × 10−8), this corresponded, for example, to a 0.35 SD decrease in pooled reading performance per log-odds in ADHD-liability (P = 9.2 × 10−5). Using subthreshold ADHD-instruments (P-threshold < 0.0015), these effects became smaller, with a 0.03 SD decrease per log-odds in ADHD risk (P = 1.4 × 10−6), although the predictive accuracy increased. However, polygenic ADHD-effects shared with EA were of equal strength and at least equal magnitude compared to those independent of EA, for all LRAs studied, and detectable using subthreshold instruments. Thus, ADHD-related polygenic links with LRAs are to a large extent due to shared genetic effects with EA, although there is evidence for an ADHD-specific association profile, independent of EA, that primarily involves literacy-related impairments.