Meta-Analysis of Cognitive Endophenotypes for ADHD

Attention-deficit/hyperactivity disorder (ADHD) is a highly heritable neurodevelopmental disorder with a complex etiology. Endophenotypes are assumed to be linked to the genetic underpinnings of complex disorders and have become a popular approach for investigating the etiology of ADHD. The aim of this study was to evaluate the utility of cognitive endophenotypes for ADHD by examining differences in performance among unaffected first-degree relatives of individuals with ADHD and non-ADHD controls. Literature searches were conducted through June 2023 using PsycINFO, PubMed, and ProQuest Dissertations and Theses databases. 40 articles met full inclusion criteria, which included performance on tasks across 10 comparable neurocognitive constructs. Multilevel meta-analysis indicated that unaffected first-degree relatives of individuals with ADHD performed significantly worse than non-ADHD controls in several domains, including working memory (Hedges’ g=0.29), processing speed (g=0.26), response time variability (g=0.40), temporal processing (g=0.30), and cognitive flexibility (g=0.20). There were no significant differences between unaffected first-degree relatives and non-ADHD controls on measures of inhibition, arousal, motor functioning, planning, and delay aversion. Substantial heterogeneity in effect sizes was explained by differences in samples, but with limited evidence of moderation by sex and age. Overall, these findings suggest that non-executive cognitive domains along with working memory may be most fruitful for linking genetic risk for ADHD to other causal factors and ultimately to the expression and continuation of ADHD symptoms.