Characterizing Biological Heterogeneity in Psychiatric and Non-psychiatric Illness

Biological heterogeneity presents a formidable challenge in understanding and improving the clinical management of psychiatric disorders. However, the extent of this heterogeneity remains to be investigated at scale or in a pan-disease setting. I will present new data characterizing biochemical and brain heterogeneity in a cohort of 445,374 individuals, considering 9 psychiatric disorders, 30 non-psychiatric chronic medical conditions, and a healthy control group. We find that heterogeneity in psychiatric illness across biochemical and brain phenotypes is 1) comparable to non-psychiatric illnesses, 2) age-dependent, and 3) misaligned with current hierarchical taxonomies of psychopathology. In schizophrenia and bipolar disorder, developmental brain markers (e.g., surface area), as well as glycemic and kidney markers (e.g., cystatin C and creatinine), were most heterogeneous, whereas lipid and hormone traits (e.g., cholesterol and sex hormone-binding globulin levels) were most variable in anxiety and depression. This work provides the first hierarchical classification of human diseases based on biological heterogeneity. Our novel characterizations of biological heterogeneity across a range of psychiatric and medical illnesses lay the groundwork for biological focal points to aid precision medicine in psychiatry.