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The contribution of attention-deficit/hyperactivity disorder polygenic load to metabolic and cardiovascular health outcomes: a large-scale population and sibling study
Ebba Du Rietz (Karolinska Institutet), Tian Xie (University Medical Center Groningen, University of Groningen), Rujia Wang (University Medical Center Groningen, University of Groningen), Rosa Cheesman (University of Oslo), Miguel Garcia‐Argibay (Örebro University, Karolinska Institutet), Zihan Dong (Karolinska Institutet), Jia Zhang (University Medical Center Groningen, University of Groningen), Jacobien Niebuur (University Medical Center Groningen, University of Groningen), Melissa Vos (University Medical Center Groningen, University of Groningen), Harold Snieder (University Medical Center Groningen, University of Groningen), Henrik Larsson (Örebro University, Karolinska Institutet), Catharina Annette Hartman (University Medical Center Groningen, University of Groningen)
Résumé : Abstract Emerging evidence suggests that ADHD is associated with increased risk for metabolic and cardiovascular (cardiometabolic) diseases. However, an understanding of the mechanisms underlying these associations is still limited. In this study we estimated the associations of polygenic scores (PGS) for ADHD with several cardiometabolic diseases and biomarkers. Furthermore, we investigated to what extent the PGS effect was influenced by direct and indirect genetic effects (i.e., shared familial effects). We derived ADHD-PGS in 50,768 individuals aged 18–90 years from the Dutch Lifelines Cohort study. Using generalised estimating equations, we estimated the association of PGS with cardiometabolic diseases, derived from self-report and several biomarkers measured during a physical examination. We additionally ran within-sibling PGS analyses, using fixed effects models, to disentangle direct effects of individuals’ own ADHD genetic risk from confounding due to indirect genetic effects of relatives, as well as population stratification. We found that higher ADHD-PGS were statistically significantly associated with several cardiometabolic diseases (R-squared [R2] range = 0.03–0.50%) and biomarkers (related to inflammation, blood pressure, lipid metabolism, amongst others) (R2 range = 0.01–0.16%) (P < 0.05). Adjustment for shared familial factors attenuated the associations between ADHD-PGS and cardiometabolic outcomes (on average 56% effect size reduction), and significant associations only remained for metabolic disease. Overall our findings suggest that increased genetic liability for ADHD confers a small but significant risk increase for cardiometabolic health outcomes in adulthood. These associations were observable in the general population, even in individuals without ADHD diagnosis, and were partly explained by familial factors shared among siblings.