Adult ADHD with comorbid major depression shows a distinguishable polygenic pattern and negative cognitive style

Attention-deficit/hyperactivity disorder (ADHD) is a highly heritable neurodevelopmental disorder, and comorbidity with other mental diseases is common. Specifically, adult ADHD (aADHD) is highly comorbid with major depressive disorder (MDD). A genetic correlation between ADHD and MDD might underlie the risk of comorbidity of both disorders. However, whether patients with ADHD and comorbid MDD differ genetically from those without comorbid MDD is currently unclear. We therefore studied the genetic background of an aADHD cohort including 352 patients with lifetime MDD and 349 patients with no history of depression, assessed by SCID-I. Polygenic risk scores for ADHD (PRS-ADHD) and MDD (PRS-MDD) were derived from large-scale genome-wide association studies. These PRS were first regressed using aADHD patients (n = 894) vs. healthy controls (n = 1026), and then using comorbidity and dimensional traits in the aADHD cohort. Both PRS-ADHD and PRS-MDD were associated with ADHD (PRS-ADHD: OR = 1.59, p < 0.0001; PRS-MDD: OR = 1.41, p < 0.0001), but only PRS-MDD was associated with comorbid MDD in aADHD patients (OR = 1.34, p < 0.001). Notably, patients with a history of combined MDD and anxiety disorders had the highest PRS-MDD. ADHD patients with a history of MDD had higher odds for other internalizing disorders, showed significantly more inattentive symptoms, higher neuroticism scores, lower childhood social confidence, and were more often treated as psychiatric inpatients. These findings suggest that comorbidity between aADHD and MDD is associated with genetic susceptibility to MDD, rather than neurodevelopmental factors intrinsic to ADHD pathophysiology. Our results also strengthen the view that comorbid MDD in aADHD is linked to an inattentive-internalizing rather than an impulsive-externalizing psychopathological factor.