Polygenic association between attention-deficit/hyperactivity disorder liability and cognitive impairments

Abstract

Background A recent genome-wide association study (GWAS) identified 12 independent loci significantly associated with attention-deficit/hyperactivity disorder (ADHD). Polygenic risk scores (PRS), derived from the GWAS, can be used to assess genetic overlap between ADHD and other traits. Using ADHD samples from several international sites, we derived PRS for ADHD from the recent GWAS to test whether genetic variants that contribute to ADHD also influence two cognitive functions that show strong association with ADHD: attention regulation and response inhibition, captured by reaction time variability (RTV) and commission errors (CE). Methods The discovery GWAS included 19 099 ADHD cases and 34 194 control participants. The combined target sample included 845 people with ADHD (age: 8–40 years). RTV and CE were available from reaction time and response inhibition tasks. ADHD PRS were calculated from the GWAS using a leave-one-study-out approach. Regression analyses were run to investigate whether ADHD PRS were associated with CE and RTV. Results across sites were combined via random effect meta-analyses. Results When combining the studies in meta-analyses, results were significant for RTV (R2 = 0.011, β = 0.088, p = 0.02) but not for CE (R2 = 0.011, β = 0.013, p = 0.732). No significant association was found between ADHD PRS and RTV or CE in any sample individually (p > 0.10). Conclusions We detected a significant association between PRS for ADHD and RTV (but not CE) in individuals with ADHD, suggesting that common genetic risk variants for ADHD influence attention regulation.

Working memory and reaction time variability mediate the relationship between polygenic risk and ADHD traits in a general population sample

“…Contrary to the well-defined impairments of inhibitory control in ADHD and previous studies indicating associations between genetic risk factors for ADHD and response inhibition [19,43,86], we found no association between response inhibition and ADHD PRSs in this sample. This is consistent with a prior study in a clinical sample [85], and suggests alternative genetic pathways, such as the influence of rare gene variants not captured in PRSs, may be involved. Measures of self-regulation including SSRT have also been called into question with regards to their utility for investigating interindividual differences [87], potentially decreasing the likelihood of identifying genetic associations.…”

“…Our results show that such relationships are also evident in a population-based sample of children, linking poorer cognitive functioning in each of the three phenotypes with increased ADHD traits. The association between higher ADHD PRSs and poorer working memory accuracy, as well as increased reaction time variability are consistent with prior findings where ADHD-PRS was significantly associated with decreased working memory in an independent cohort [11], and other studies linking dysfunctions of these mechanisms to ADHD genetic risk factors [3,84,85], providing further weight to the conceptualisation of working memory and reaction time variability as endophenotypes for ADHD. Partial mediation observed for working memory and a measure of topdown regulation of attention (reaction time variability) confirms previous results from a case-control study [42], but contrasts the full mediation identified for working memory linking ADHD PRSs and symptoms of hyperactivity/impulsivity [14], suggesting that gene-cognition-trait relationships might differ between ADHD symptom domains.…”

Working memory and reaction time variability mediate the relationship between polygenic risk and ADHD traits in a general population sample

“…21, 22, 25 Our results show that such relationships are also evident in a populationbased sample of children, linking poorer cognitive functioning in each of the three phenotypes with increased ADHD traits. The association between higher ADHD PRSs and poorer working memory accuracy as well as increased reaction time variability are consistent with prior findings where ADHD-PRS was significantly associated with decreased working memory in an independent cohort, 11 and other studies linking dysfunctions of these mechanisms to ADHD genetic risk factors, 3, 82, 83 providing further weight to the conceptualisation of working memory and reaction time variability as endophenotypes for ADHD. Partial mediation observed for working memory confirms previous results from a case-control study, 42 but contrasts the full mediation identified for working memory linking ADHD PRSs and symptoms of hyperactivity/impulsivity, 14 suggesting that gene-cognition-trait relationships might differ between ADHD symptom domains.…”

Insights into attention-deficit/hyperactivity disorder from recent genetic studies

“…Studies have also examined the impact of ADHD-PRS on outcomes in clinical ADHD samples. Collectively, they suggest that PRS do not just capture risk for ADHD diagnosis but may also be a marker of phenotypic severity in individuals with ADHD, showing association with a wide range of comorbid phenotypes, including CD (Demontis et al, 2021; Hamshere et al, 2013), irritability/emotional dysregulation (Nigg et al, 2020; Riglin et al, 2017), severity of clinical profile (Vuijk et al, 2020), executive function difficulties (working memory, inhibitory control, and response variability) (Chang, Yang, Wang, & Faraone, 2020; Nigg et al, 2018; Vainieri et al, 2021), and SUDs (i.e. alcohol and cannabis use disorders) (Wimberley et al, 2020).…”