Heritability and polygenic load for combined anxiety and depression

Abstract Anxiety and depression commonly occur together resulting in worse health outcomes than when they occur in isolation. We aimed to determine whether the genetic liability for combined anxiety and depression was greater than when anxiety or depression occurred alone. Data from 12,558 genotyped twins (ages 38-85) were analysed, including 1,986 complete monozygotic and 1,809 complete dizygotic pairs. Outcomes were prescription of antidepressant and anxiolytic drugs, as demined by the World Health Organization Anatomical Therapeutic Chemical Classimication System (ATC) convention, for combined anxiety and depression ( n = 1054), anxiety only ( n = 744), and depression only ( n = 511). Heritability of each outcome was estimated using twin modelling, and the inmluence of common genetic variation was assessed from polygenic scores (PGS) for depressive symptoms, anxiety, and 40 other traits. Heritability of combined anxiety and depression was 79% compared with 41% for anxiety and 50% for depression alone. The PGS for depressive symptoms likewise predicted more variation in combined anxiety and depression (adjusted odds ratio per SD PGS = 1.53, 95% CI = 1.43-1.63; Δ R 2 = .031, ΔAUC = .044) than the other outcomes, with nearly identical results when combined anxiety and depression was demined by International Classimication of Diseases (ICD) diagnoses (adjusted odds ratio per SD PGS = 1.70, 95% CI = 1.53-1.90; Δ R 2 = .036, ΔAUC = .051). Individuals in the highest decile of PGS for depressive symptoms had over 5 times higher odds of being prescribed medication for combined anxiety and depression compared to those in the lowest decile. We conclude that genetic factors explain substantially more variation in combined anxiety and depression than anxiety or depression alone.