To Örebro University

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) and major depressive disorder (MDD) are two highly prevalent disorders that frequently co-occur. Prior evidence from genetic and cohort studies supports an association between ADHD and MDD. However, the direction and mechanisms underlying their association remain unclear. As ADHD onsets in early life, it has been hypothesized that ADHD may cause MDD.

METHODS: In this study, we examined the association of ADHD with MDD using three different genetically informed methods to disentangle causality from confounding: 1) a nationwide longitudinal register-based full sibling comparison (N=1,018,489) adjusting for shared familial confounding; 2) a prospective co-twin control study comprising 16,447 twins (5,084 monozygotic and 11,393 dizygotic); and 3) a two-sample Mendelian randomization analysis using the largest available ADHD (N=225,534) and MDD (N=500,199) genome wide association (GWAS) summary statistics, adjusting for correlated and uncorrelated horizontal pleiotropy.

RESULTS: Sibling and twin comparisons indicated that individuals with ADHD have an increased risk for subsequent development of MDD (HR=4.12 [3.62-4.69]) after adjusting for shared genetic and familial factors, and that ADHD scores endorsed by parents are positively associated with subsequent MDD scores at ages 15 and 18 years (b=0.07 [0.05-0.08]) and b=0.09 [0.08-0.11], respectively). Mendelian randomization analyses showed that genetic liability for ADHD is causally related to MDD (OR=1.15 [1.08-1.23]).

CONCLUSIONS: Our study provided consistent results across three different genetically informative approaches, strengthening the hypothesis that ADHD is causally related to MDD.