JAMA Psychiatry. 2025 Jul 9. doi: 10.1001/jamapsychiatry.2025.1289. Online ahead of print.
ABSTRACT
IMPORTANCE: The etiologic interrelationship of 4 rare/controversial psychotic disorders (delusional disorder [DD], acute psychoses [AP], psychosis not otherwise specified [PNOS], and schizoaffective disorder [SAD]) is poorly understood.
OBJECTIVE: To assess levels of the family genetic risk score (FGRS) for schizophrenia (SZ), bipolar disorder (BD), and major depression (MD) in individuals with DD, AP, PNOS, and SAD, thereby clarifying their genetic relationships.
DESIGN, SETTING, AND PARTICIPANTS: This cohort study included all individuals born in Sweden between 1950 and 2000 to Swedish-born parents followed up until 2018 with diagnoses of MD, BD, SZ, SAD, AP, PNOS, and DD, based on diagnosis codes from national registries.
EXPOSURES: FGRS for SZ, BD, and MD calculated from first- through fifth-degree relatives, controlling for cohabitation.
MAIN OUTCOMES AND MEASURES: Diagnoses of DD, AP, PNOS, and SAD.
RESULTS: In the cohort, 667 012 individuals had MD (420 142 females [63%] and 246 870 males [37.0%]), 58 385 had BD (36 344 females [62%] and 22 041 males [38%]), 17 465 had SZ (6330 females [36%] and 11 135 males [64%]), 7597 had SAD (4125 females [54%] and 3472 males [46%]), 16 315 had AP (7907 females [49%] and 8408 males [51%]), 27 127 had PNOS (12 277 females [45%] and 14 850 males [55%]), and 11 560 had DD (5060 females [44%] and 6500 males [56%]). On “genetic maps” of SZ FGRS, BD FGRS, and MD FGRS, DD stood alone with approximately half the genetic risk for SZ compared with SZ cases and similar levels of BD and MD risk. SAD was also distinct as the only disorder with quite high genetic risks for both SZ and BD and was clearly separable from psychotic BD. AP and PNOS had similar genetic profiles with levels of SZ FGRS similar to DD but higher levels of genetic risk for BD and MD. Subdividing psychoses by outcome produced minimal effects on the DD genetic profile, moderate effects on AP and PNOS, and large effects on SAD, with good social outcomes associated with decreased SZ FGRS and increased BD FGRS.
CONCLUSIONS AND RELEVANCE: In a Swedish population, none of the 4 disorders appeared, from a genetic perspective, to be subtypes of SZ, BD, or MD. Further genetics research on the syndromes of DD, AP, PNOS, and SAD have much to teach about the relationship between dimensions of genetic risks and the clinical presentation and course of psychotic illness.
PMID:40632548 | DOI:10.1001/jamapsychiatry.2025.1289
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