Decomposing genetic effects of social connectedness and depression on youth behaviors and long-term clinical outcomes.

Importance: Lacking social connectedness is associated with broad morbidity. Yet the underlying mechanisms remain obscures, especially given its entanglement with depressive symptoms. Clarifying whether social connectedness confers unique risk beyond depression can guide clinical care and social infrastructure interventions. Objective: To decompose shared genetic architecture between social connectedness and depressive affect, derive independent polygenic liabilities, and test their differential associations with youth behaviors, digital engagement, and adult clinical outcomes. Design Setting and Participants: Using summary statisitcs from eight genome-wide association studies (GWAS) on social connectedness related traits, we extracted two orthogonal latent genetic factors: a depression related factor (DEP) and a social disconnection factor (SOC). We performed GWAS-by-subtraction to obtain single nucleotide polymorphisms (SNP) level effect sizes and then constructed factor specific polygenic scores (PGS) in (i) a multi-site longitudinal youth cohort (Adolescent Brain Cognitive Development Study, ABCD, questionnaire set n=11,378; EARS smartphone subsample n=914) and (ii) a large scale electronic health record adult cohort (All of Us Research Program, AoU, n=402,944). We evaluated their relative contributions to youth's psychopathology, prosocial behaviors, screen time use, and adult's clinical outcomes. Results: In GWAS-by-subtraction, SOC has a GWAS significant loci on Conclusions and Relevance: Social connectedness and depressive affect are highly correlated yet genetically separable with distinct behavioral and clinical profiles. Addressing both may be necessary to reduce the health burden associated with the rising reports on loneliness.