Disentangling genetically confounded polygenic associations between Attention-Deficit/Hyperactivity Disorder, literacy and language

Abstract

Interpreting polygenic overlap between ADHD and both literacy- and language-related impairments is challenging as genetic confounding can bias associations. Here, we investigate evidence for links between polygenic ADHD risk and multiple literacy- and language-related abilities (LRAs), assessed in UK children (N[≤]5,919), conditional on genetic effects shared with educational attainment (EA). Genome-wide summary statistics on clinical ADHD and years-of-schooling were obtained from large consortia (N[≤]326,041). ADHD-polygenic scores (ADHD-PGS) were inversely associated with LRAs in ALSPAC, most consistently with reading-related abilities, and explained [≤]1.6% phenotypic variation. Polygenic links were then dissected into both genetic effects shared with and independent of EA using multivariable regressions (MVR), analogous to Mendelian Randomization approaches accounting for mediating effects. Conditional on EA, polygenic ADHD risk remained associated with multiple literacy-related skills, phonemic awareness and verbal intelligence, but not language-related skills such as listening comprehension and non-word repetition. Pooled reading performance showed the strongest overlap with ADHD independent of EA. Using conservative ADHD-instruments (P-threshold<5x10-8) this corresponded to a 0.35 decrease in Z-scores per log-odds in ADHD-liability (P=9.2x10-5). Using subthreshold ADHD-instruments (P-threshold<0.0015), these associations had lower magnitude, but higher predictive accuracy, with a 0.03 decrease in Z-scores (P=1.4x10-6). 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 only detectable using subthreshold instruments. Thus, ADHD-related polygenic links are highly susceptible to genetic confounding, concealing an ADHD-specific association profile that primarily involves reading-related impairments, but few language-related problems.