Abstract
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.
Highlights
Introduction Children with AttentionDeficit/Hyperactivity Disorder (ADHD) often experience difficulties mastering literacyrelated and/or language-related abilities (LRAs)[1,2,3]
Further twin research suggests that the genetic covariance between reading difficulties and AttentionDeficit/Hyperactivity Disorder (ADHD) is largely independent of genetic factors shared with IQ19, it is not known whether these findings extend to a wider spectrum of LRAs, beyond reading abilities
Applying multivariable regression (MVR) techniques, analogous to Mendelian Randomisation (MR) approaches[26], we report here disentangled associations between polygenic ADHD risk and LRA measures and estimate effects independent of and shared with genetically predicted years of schooling, using summary statistics from the Social Science Genetic Association Consortium (SSGAC)
Summary
Introduction Children with AttentionDeficit/Hyperactivity Disorder (ADHD) often experience difficulties mastering literacyrelated and/or language-related abilities (LRAs)[1,2,3]. The spectrum of affected LRAs in ADHD may, Verhoef et al Translational Psychiatry (2019)9:35 include writing[5,6], spelling[7,8], syntactic[9,10] and phonological[9,10] abilities. To interpret the comorbidity of ADHD and RD, a multiple-deficit model including shared underlying aetiologies has been proposed, involving both genetic and environmental influences[15]. This model is supported by twin studies suggesting that the co-occurrence of ADHD symptoms and reading deficits is, to a large extent, attributable to shared genetic influences[16,17,18]. Predicted EA is a genetic proxy of cognitive abilities, and socioeconomic status[20] including, for example, associations with maternal smoking during pregnancy, parental smoking, household income or watching television[24]
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