Interleukin pathway genotype and the grandiosity dimension of psychosis: a machine learning gene set analysis with unsupervised anomaly detection controls

Immune involvement in psychosis is well supported, although most of the evidence comes from studies of negative and deficit symptoms. Grandiosity, in comparison, has received little attention. It is, however, the one symptom for which the two main accounts of inflammation in psychosis, activation and reward blunting, make opposite predictions. We tested these predictions in 489 patients with schizophrenia from the Poznań cohort, genotyped for 26 functional variants in eight interleukin-pathway genes and rated with the Operational Criteria Checklist (OPCRIT). Grandiosity was scored from the two OPCRIT items for inflated self-esteem and grandiose delusions. The panel was first tested as a whole, and each gene was then analyzed as a set with the sequence kernel association test (SKAT), with false-discovery-rate control and selection-adjusted permutation. For any gene that passed, we localized the signal within it and estimated the effect with Firth penalized logistic regression. Its stability was examined by held-out splits, jackknife, fragility analysis, comparison with five other symptom dimensions, and anomaly detection. The panel as a whole did not predict grandiosity (out-of-fold Spearman rho = 0.041, permutation p = 0.159). One gene, IL10, showed an association (SKAT p = 0.0028, q = 0.023; selection-adjusted p = 0.025), which was confined to the -819/-592 promoter locus. Carriers of two copies had a Firth odds ratio of 5.28 (95% CI 2.37 to 12.48, p = 4.5 × 10^-5), consistent with a recessive effect, and 65% of the 26 carriers had grandiosity, against 24% of non-carriers. The effect was specific to grandiosity (standardized beta 0.19, p = 2 × 10^-5) and moderately reproducible across split halves (r = 0.36; mania control r = 0.03). It did not depend on sex, age, or age at onset, and it was unchanged under alternative SKAT kernels, under panel principal components, and after adjustment for neuroleptic response. Two-copy carriage did not differ between the 466 cases and 482 controls. We propose a recessive IL10 -819/-592 effect specific to grandiosity as a hypothesis for independent replication.