Do more risk genes mean more severe schizophrenia?

Researchers compared 346 people hospitalized continuously for at least five years with treatment-resistant schizophrenia against more than 18,000 others. Each standard-deviation rise in schizophrenia polygenic score raised the odds of being in that most severe group by 40% to 80%.

More than one in five people with schizophrenia get little or no benefit from antipsychotic medication, and a smaller group stays severely ill for years on end. Researchers asked whether that most severe form carries a heavier load of the common genetic variants linked to schizophrenia. They recruited 346 people of European ancestry from Pennsylvania state psychiatric hospitals who met a strict definition: at least five years of continuous hospitalization, active treatment, and no response to three or more antipsychotics. They compared them with 10,757 people with treatment-resistant schizophrenia, 1,148 with schizophrenia generally, and 6,320 people without psychiatric diagnoses, drawn from cohorts in the US, Sweden, and the UK, for 18,571 people in total. For each standard-deviation increase in schizophrenia polygenic score, the odds of being in the continuously hospitalized group rose by 40% to 80% relative to the other schizophrenia groups. A smaller exploratory analysis in 476 people of African ancestry (78 cases) pointed in the same direction with weaker statistical support. The pattern held after accounting for sex and after excluding people with additional diagnoses. Limits worth naming: the comparison groups came from different countries and recruitment settings, which can introduce differences that have nothing to do with genetics; the effect describes group averages rather than any individual's prognosis; and polygenic scores still perform poorly outside European-ancestry samples.