Disentangling polygenic associations between attention-deficit/hyperactivity disorder, educational attainment, literacy and language

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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.

Adolescent, Attention Deficit Disorder with Hyperactivity, Child, Educational Status, Female, Genome-Wide Association Study, Humans, Intelligence, Language, Literacy, Male, Multifactorial Inheritance, Multivariate Analysis, Polymorphism, Single Nucleotide, Psychiatric Status Rating Scales, Regression Analysis, Risk Assessment, United Kingdom
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Translational Psychiatry
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Springer Nature
British Heart Foundation (None)
Medical Research Council (MC_UU_00002/7)
British Heart Foundation (RG/18/13/33946)
Wellcome Trust (204623/Z/16/Z)
The UK Medical Research Council and the Wellcome Trust (Grant ref: 102215/2/13/2) and the University of Bristol provide core support for ALSPAC. The ALSPAC GWAS data was generated by Sample Logistics and Genotyping Facilities at the Wellcome Trust Sanger Institute and LabCorp (Laboratory Corporation of America) using support from 23andMe. This research was facilitated by the Social Science Genetic Association Consortium (SSGAC) and Psychiatric Genomics Consortium (PGC) by providing access to genome-wide summary statistics. This publication is the work of the authors and E.V. and B.S.T.P. will serve as guarantors for the contents of this paper. E.V., C.Y.S., B.S.T.P. and S.E.F. are supported by the Max Planck Society. The iPSYCH project is funded by the Lundbeck Foundation (grant no R102-A9118 and R155−014−1724) and the universities and university hospitals of Aarhus and Copenhagen. Genotyping of iPSYCH and PGC samples was supported by grants from the Lundbeck Foundation, the Stanley Foundation, the Simons Foundation (SFARI 311789 to M.J.D.), and NIMH (5U01MH094432−02 to M.J.D.). The Danish National Biobank resource was supported by the Novo Nordisk Foundation. Data handling and analysis was supported by NIMH (1U01MH109514−01 to Michael O’Donovan and Anders D Børglum). High-performance computer capacity for handling and statistical analysis of iPSYCH data on the GenomeDK HPC facility was provided by the Centre for Integrative Sequencing, iSEQ, Aarhus University, Denmark (grant to Anders D Børglum).