Genetic contribution to developmental psychopathology in offspring with familial risk for bipolar disorder

Major mood disorders aggregate within families, often manifesting as childhood psychopathology, including attention-deficit/hyperactivity disorder (ADHD) and anxiety disorders that negatively predict treatment outcomes. We aimed to test if familial risk for bipolar disorder and its childhood-onset antecedents (ADHD and anxiety) differentiates subtypes of mood disorder risk with distinct genetic profiles. Seven longitudinal cohorts have prospectively assessed 1065 participants, including 660 offspring of parents with bipolar disorder through age 21.7 (range=8.0-36.5, SD=5.11) with a follow-up duration of 6.4 years (SD=5.66). Polygenic scores (PGS) estimate genetic liability for depression, bipolar disorder, anxiety, ADHD, neuroticism, and addiction risk. Mixed-effects and Cox regression models examine relationships between PGS, childhood psychopathology, mood disorder onset, and familial risk for bipolar disorder. Among offspring of unaffected parents, increased ADHD, and neuroticism PGSs were associated with ADHD (β=0.46, 95%CI[0.03-0.89]) and anxiety disorders(β=0.29, 95%CI[0.05-0.54]), respectively. Comorbid ADHD and anxiety also increased PGS for neuroticism (β=0.55, 95%CI[0.07-1.02]), ADHD(β=0.64, 95%CI[0.14-1.15]), and bipolar disorder(β=0.67, 95%CI[0.18-1.15]) in absence of familial risk. Offspring of parents with bipolar disorder did not have psychopathologies associated with PGSs.In offspring without family risk, PGS for anxiety (HR=10.67, 95%CI[2.76-41.21]), depression(HR=2.86, 95%CI[1.35-6.04]) and neuroticism(HR=3.48, 95%CI[1.49-8.14]) were associated with major mood disorder onset when comorbid ADHD and anxiety was present. PGS for neuroticism (HR=1.58, 95%CI[1.08-2.32]) and addiction(HR=1.49, 95%CI[1.06-2.09]) also predicted onset in offspring without familial risk and anxiety. Additionally, PGS for addiction was associated with mood disorder onset when no familial risk or childhood antecedents were present (HR=1.71, 95%CI[1.18-2.46]).PGS for ADHD predicted mood disorder onset in offspring with familial risk and anxiety (HR=1.26, 95%CI[1.03-1.55]). In offspring of parents with bipolar disorder, PGS for addiction was only associated with major mood disorder onset in the presence of comorbid ADHD and anxiety (HR=1.40, 95%CI[1.05-1.88]). Childhood-onset comorbidities in offspring with familial risk for bipolar disorder have unique genetic etiology contributing to mood disorder risk.