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. 2025 Aug 8;15(1):29003.
doi: 10.1038/s41598-025-14438-6.

Exposotypes in psychotic disorders

Walid Yassin  1   2 , Bryan Kromenacker  3 , James B Green  4   5 , Carol A Tamminga  3 , Elisabetta C Del Re  4   6   7 , Pegah Seif  4   7 , Cuihua Xia  8   9 , Ney Alliey-Rodriguez  8   10 , Elliot S Gershon  8 , Brett A Clementz  11 , Godfrey D Pearlson  12   13 , Sarah K Keedy  8 , Elena I Ivleva  3 , Scott Kristian Hill  8   14 , Jennifer E McDowell  11 , Matcheri S Keshavan  15   16
Affiliations

Exposotypes in psychotic disorders

Walid Yassin et al. Sci Rep. .

Abstract

Psychiatry lags in adopting etiological approaches to diagnosis, prognosis, and outcome prediction compared to the rest of medicine. Etiological factors such as childhood trauma (CHT), substance use (SU), and socioeconomic status (SES) significantly affect psychotic disorder symptoms. This study applied an agnostic clustering approach to identify exposome clusters "Exposotypes (ETs)" and examine their relationship with clinical, cognitive, and functional outcomes. Using data from individuals with psychotic disorders (n = 1,350), and controls (n = 623), we assessed the relationship between the exposotypes and outcomes. Four exposotypes were identified: ET1 characterized by high CHT and SU; ET2, high CHT; ET3, high SU; ET4, low exposure. Compared to ET4, ET1 demonstrated higher positive and general symptoms, anxiety, depression, impulsivity, and mania; ET2 had higher anxiety, depression, and impulsivity; ET3 had better cognitive and functional outcomes with lower negative symptoms. Intracranial volume was largest in ET3, and smallest in ET2. No group differences in schizophrenia polygenic risk scores were found. The age of onset was 5 years earlier in ET1 than in ET4. These findings provide insight into the complex etiological interplay between trauma, and SU, as well as their unique effects on clinical symptoms, cognition, neurobiology, genetic risk, and functioning.

Keywords: Childhood trauma; Cognitive function; Machine learning; Psychotic disorders; Socioeconomic status; Substance use.

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Conflict of interest statement

Declarations. Competing interests: Dr. Clementz reports being on the KyNexis SAB and the B-SNIP Diagnostics, LLC Board of Managers.Dr. McDowell reports serving on the B-SNIP Diagnostics, LLC Board of ManagersDr. Keedy reports serving on the B-SNIP Diagnostics, LLC Board of ManagersDr. Ivleva reports serving on the B-SNIP Diagnostics, LLC Board of Managers. She also served on scientific advisory boards for Janssen Scientific Affairs, LLC, Alkermes, Inc and Karuna Therapeutics.Dr. Gershon reports serving on the B-SNIP Diagnostics, LLC Board of ManagersDr. Keshavan reports serving on the B-SNIP Diagnostics, LLC Board of ManagersDr. Pearlson reports serving on the B-SNIP Diagnostics, LLC Board of ManagersDr. Tamminga reports serving on the Merck DSmB, being on the Karuna SAB and owning Karuna stock, and being on the KyNexis SAB and owning KyNexis stock, and B-SNIP Diagnostics, LLC Board of Managers.Other authors have no competing interests to declare.

Figures

Fig. 1
Fig. 1
(a) Substance use. (b) Trauma. (c) Socioeconomic status. ET: Exposotype, Alc: Alcohol Use, Can: Cannabis Use, Fam: Family, PT: Patient. For all pairwise testing: ***: p < 0.001, **: p < 0.01, * p < 0.05.
Fig. 2
Fig. 2
(a-c) Clinical outcomes and pairwise comparisons for psychotic disorders sample. (a) PANSS. (b) Other clinical. (c) Functioning. ET: Exposotype, PANSS: Positive and Negative Syndrome Scale, Anxiety: Clinical Anxiety Scale, Depression: Montgomery-Asberg Depression Rating Scale, Mania: Young Mania Rating Scale, Impulsivity: Barratt Impulsiveness Scale, GAF: Global Assessment of Functioning. For all pairwise testing: ***: q < 0.001, **: q < 0.01, * q < 0.05.
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