Investigating the relationship between attention-deficit hyperactivity disorder (ADHD) and C-reactive protein (CRP): observational, polygenic risk score, and Mendelian randomization analyses

Abstract Background Emerging evidence suggests a co-occurrence of attention-deficit hyperactivity disorder (ADHD) and immune response-related conditions. However, it is unclear whether there is a causal relationship between ADHD and immune response. Methods We investigated the associations between ADHD traits, common variant genetic liability to ADHD, and serum C-reactive protein (CRP) levels in childhood and adulthood, using data from the Avon Longitudinal Study of Parent and Children. Genetic correlation was estimated using linkage-disequilibrium score regression. Two-sample Mendelian randomization (MR) was conducted to test potential causal effects of ADHD genetic liability on serum CRP as an indicator of systemic inflammation, as well as the genetically proxied levels of specific plasma cytokines. Results There was little evidence to suggest association between ADHD and CRP in childhood and adulthood. ADHD genetic liability was associated with a higher serum CRP at ages 9 ( β = 0.02, 95% confidence interval [CI] = 0, 0.03), 15 ( β = 0.04; 95% CI = 0.02, 0.06), and 24 years ( β = 0.03; 95% CI = 0.01, 0.05). There was evidence of genetic correlations between ADHD and CRP ( $ {r}_g $ = 0.27; 95% CI = 0.19, 0.35). Evidence of a bidirectional effect of genetic liability to ADHD and CRP was found by two-sample MR (ADHD-CRP: β IVW = 0.04, 95% CI = 0.01, 0.07; CRP-ADHD: OR IVW = 1.09, 95% CI = 1.01, 1.17). Conclusions Further work is necessary to understand the biological pathways linking ADHD genetic liability and CRP and gain insights into understanding how they might contribute in the links between ADHD and later-life adverse physical and mental health outcomes.