Fig. 3.

Rare variant burden analyses in schizophrenia relevant gene sets. Enrichment of qualifying missense (A) and loss-of-function variants (B) across gene sets of relevance to schizophrenia in individuals with severe, extremely treatment-resistant schizophrenia compared to healthy controls. Unadjusted exact two-sided Cochran–Mantel–Haenszel P values, effect sizes between severe, extremely treatment-resistant schizophrenia and healthy controls represented as odds ratios, and horizontal bars indicating 95% CIs are shown. Gene sets are described in detail in Fig. 1 and SI Appendix. All OMIM: All genes associated with Mendelian disorders in the OMIM database. Non-OMIM: Missense and loss-of-function intolerant genes without a known disease association in OMIM. Behav OMIM: The subset of OMIM genes with clinical phenotype annotations including “behavioral” manifestations. SCHEMA Miss Intol: Genes with prior evidence of enrichment for missense variation in the schizophrenia exome meta-analysis (SCHEMA) study of schizophrenia. SCHEMA LoF Intol: Genes with prior evidence of enrichment for loss-of-function variation in SCHEMA. ASD/DD: combined gene set of 102 genome-wide significant genes associated with autism spectrum disorder and 299 genome-wide significant genes associated with developmental delay. All gene sets ending with “Miss Intol” are restricted to include only those overlapping intolerant genes with a missense Z > 3.09 and those ending in “LoF Intol” overlapping genes with probability of loss-of-function intolerance (pLI) score > 0.9. *FDR < 0.1.