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Interplay of ADHD polygenic liability with birth-related, somatic and psychosocial factors in ADHD - a nationwide study

Background: ADHD is multifactorial, yet the interplay ADHD polygenic risks scores (ADHD-PRS) and other ADHD associated risk-factors remains relatively unexplored. The aim of this study was to investigate associations, confounding and interactions of ADHD-PRS with birth, somatic and psychosocial risk-factors previously associated with ADHD. Methods: Participants came from the Danish iPSYCH2012 case-cohort, including a randomly selected general population sample (N=21,578), and all ADHD cases with an ICD-10 diagnosis F90.0 (N=13,697), born in Denmark 1981-2005. We derived ADHD-PRS and identified 25 ADHD risk-factors in Danish national registers. Logistic regression was used to estimate associations of ADHD-PRS with each risk-factors in the general population. Cox models were applied in the full case-cohort to evaluate confounding of risk-factor associations by ADHD-PRS and family psychiatry history, and interactions between ADHD-PRS and each risk-factor. Results: ADHD-PRS was associated with 14 out of 25 ADHD risk-factors in the general population, e.g., maternal autoimmune disorder, mild traumatic brain injury (TBI), and most psychosocial risk-factors. In the full case-cohort, 21 risk-factors were associated with ADHD diagnosis. Adjusting for ADHD-PRS and parental psychiatric history only led to minor attenuations of these associations. Interactions were observed between ADHD-PRS and sex, maternal autoimmune disease, TBI, paternal employment and age at child-birth. Conclusion: Higher ADHD-PRS is associated with exposure to certain birth and somatic ADHD risk-factors, and broadly to psychosocial adversity. Evidence of gene-environment interactions were weak and ADHD-PRS and/or family psychiatric history have limited confounding effect on ADHD risk-factor associations, suggesting that majority of the investigated risk-factors act largely independently of ADHD-PRS to increase risk of ADHD.