Convergent Penetrance: Quantitative Evidence for a Shared Genetic Substrate of Psychiatric Disorders and Cancer

This work is conceptually related to the author’s earlier NOAH6 publications, but is presented here as an independent, self-contained population-level analysis. Abstract Traditional models of genetic predisposition in medicine are most often based on the paradigm of specific genes for specific diseases. This paper presents an alternative, hierarchical model, grounded in the empirical observation that offspring of parents with psychiatric disorders and offspring of parents with cancer exhibit surprisingly similar patterns of incomplete penetrance within their respective domains. Through a synthesis of large meta-analyses (in total >3 million offspring at psychiatric risk) and national cancer registries (the Swedish Family-Cancer Database, >10 million individuals), this work quantifies that convergence. The analysis demonstrates that the absolute lifetime risk for a specific outcome (the same psychiatric disorder or the same cancer) in offspring of affected parents converges in a mid-range of approximately 10–35%, with relative risks (RR / SIR ≈ 1.5–3.0) in both domains. Furthermore, the risk of developing any severe outcome within the psychiatric or oncologic domain reaches 30–55%. These quantitatively similar, polygenic inheritance patterns, together with evidence of transdiagnostic overlap and shared genetic architecture from existing studies, indicate the potential existence of a common upstream substrate—an inherited predisposition to systemic regulatory instability. This substrate, formalized within the NOAH6 (Neural Overdrive Alarm Hierarchy) framework as a hypothetical model, may manifest through different downstream pathways: earlier and functional (psychiatric disorders) or later and structural (cancers). Existing genomic evidence supports pleiotropic variants and shared pathways spanning immune regulation, metabolic regulation, and stress-response biology, though robust cross-domain familial risks remain limited and require further investigation. The paper concludes that a substantial proportion of familial cases in both domains may arise from this general polygenic vulnerability rather than from rare disease-specific mutations, necessitating a shift toward regulatory-oriented prevention strategies, pending validation.