Publications

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.

Abstract

Neurodevelopmental disorders are defined by highly heritable problems during development and brain growth. Attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorders (ASDs), and intellectual disability (ID) are frequent neurodevelopmental disorders, with common comorbidity among them. Imaging genetics studies on the role of disease-linked genetic variants on brain structure and function have been performed to unravel the etiology of these disorders. Here, we reviewed imaging genetics literature on these disorders attempting to understand the mechanisms of individual disorders and their clinical overlap. For ADHD and ASD, we selected replicated candidate genes implicated through common genetic variants. For ID, which is mainly caused by rare variants, we included genes for relatively frequent forms of ID occurring comorbid with ADHD or ASD. We reviewed case-control studies and studies of risk variants in healthy individuals. Imaging genetics studies for ADHD were retrieved for SLC6A3/DAT1, DRD2, DRD4, NOS1, and SLC6A4/5HTT. For ASD, studies on CNTNAP2, MET, OXTR, and SLC6A4/5HTT were found. For ID, we reviewed the genes FMR1, TSC1 and TSC2, NF1, and MECP2. Alterations in brain volume, activity, and connectivity were observed. Several findings were consistent across studies, implicating, for example, SLC6A4/5HTT in brain activation and functional connectivity related to emotion regulation. However, many studies had small sample sizes, and hypothesis-based, brain region-specific studies were common. Results from available studies confirm that imaging genetics can provide insight into the link between genes, disease-related behavior, and the brain. However, the field is still in its early stages, and conclusions about shared mechanisms cannot yet be drawn.