Ultra-rare coding variants in schizophrenia risk genes are associated with longitudinal phenotypic differences across psychotic disorders

Ultra-rare damaging variants in schizophrenia risk genes in the SUPER-Finland psychosis cohort are linked to earlier hospital admissions and worse longitudinal clinical and functional trajectories despite similar diagnoses.

• Why it matters: SCHEMA identified 40 schizophrenia risk genes, but it was unclear whether carriers show distinct illness courses across the psychosis spectrum beyond schizophrenia diagnosis alone.
• What they did: The study screened 9,821 sequenced psychotic-disorder participants for damaging ultra-rare variants in 40 SCHEMA genes, yielding 163 carriers, then used nationwide register data plus enrollment interviews, questionnaires, and cognitive tests.
• The result: Carriers had earlier psychiatric (HR=2.30 [1.48-3.57], p=2.05e-04) and non-psychiatric (HR=1.40 [1.10-1.79], p=6.88e-03) admissions, greater childhood adversity, poorer neuropsychological performance, and less favorable longitudinal trajectories, clustering with high SZ-PGS (≥90th percentile).

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