Unweaving the web: Polygenic influences on networks of psychopathology symptoms

Objective: Polygenic risk score (PRS) studies commonly employ a disorder-level approach to phenotyping, implicitly considering psychiatric disorders as homogenous constructs. However, symptom heterogeneity is ubiquitous, with many possible combinations of symptoms falling under the same disorder umbrella. Focusing on individual symptoms can shed a new light on the role of genetics in the aetiology of psychopathology and comorbidity, by establishing (i) whether PRS associate with all symptoms of psychiatric disorders, or with a subset of core indicators; (ii) whether PRS associate with comorbid phenotypes via specific sets of relevant symptoms.Methods: Networks of symptoms and PRS were estimated in a sample from the Avon Longitudinal Study of Parents and Children (ALSPAC), including PRS for depression, anxiety, attention deficit-hyperactivity disorder (ADHD), body mass index (BMI) and educational attainment. Following pre-registered analyses, models were cross-validated in an independent sample from the Twins Early Development Study (TEDS).Results: Findings first indicate that PRS do not uniformly associate with all symptoms within psychopathology measures and instead associate primarily with restricted subsets. This suggests that polygenic risk may primarily influence core psychopathology symptoms and indirectly propagate to others. Second, psychiatric PRS associate with specific cross-disorder symptoms, while non-psychiatric PRS associate with a variety of indicators across disorders, suggesting a potential contribution of non-psychiatric traits to comorbidity. Patterns of associations also suggest pathways linking polygenic risk to psychopathology in childhood.Conclusions: Genetic associations observed at the disorder level may hide symptom-level heterogeneity. A symptom-level approach enables a better understanding of the role of polygenic risk in shaping psychopathology and comorbidity.