Biochemical and brain heterogeneity characterizes psychiatric and non-psychiatric illness

Biological heterogeneity presents a formidable challenge in understanding psychiatric illness, yet it remains underexplored at scale or in a pan-disease setting. We characterized biochemical and brain heterogeneity in 445,374 individuals, considering 9 psychiatric disorders and 30 non-psychiatric medical conditions. Psychiatric and non-psychiatric illnesses were characterized by greater biological heterogeneity than predicted by healthy variation. Notably, heterogeneity in psychiatric disorders was comparable to non-psychiatric illnesses and often diverged from diagnostic classification. Circulating glucose and glycated hemoglobin levels were the most heterogeneous traits in 65% of diagnoses, suggesting that glucose dysregulation is pervasive yet variable across diseases. Diagnosis-specific patterns also surfaced-e.g., in schizophrenia, developmental brain markers ranked among the most heterogeneous traits. These characterizations of biochemical and brain heterogeneity lay the groundwork for biological focal points to aid precision psychiatry research. To support this effort, we provide an interactive online resource for exploring and downloading illness-specific heterogeneity measures.