Ultrarare Missense Variants Implicated in Utah Pedigrees Multiply Affected With Schizophrenia

Recent work from the Schizophrenia Exome Sequencing Meta-analysis (SCHEMA) consortium showed significant enrichment of ultrarare variants in schizophrenia cases. Family-based studies offer a unique opportunity to evaluate rare variants because risk in multiplex pedigrees is more likely to be influenced by the same collection of variants than an unrelated cohort.

Here, we examine whole genome sequencing data from 35 individuals across 6 pedigrees multiply affected by schizophrenia. We applied a rigorous filtering pipeline to search for classes of protein-coding variants that cosegregated with disease status, and we examined these for evidence of enrichment in the SCHEMA dataset. Additionally, we applied a family-based consensus approach to call copy number variants and screen against a list of schizophrenia-associated risk variants.

We identified deleterious missense variants in 3 genes (ATP2B2, SLC25A28, and GSK3A) that cosegregated with disease in 3 of the pedigrees. In the SCHEMA, the gene ATP2B2 shows highly suggestive evidence for deleterious missense variants in schizophrenia cases (p = .000072). ATP2B2 is involved in intracellular calcium homeostasis, expressed in multiple brain tissue types, and predicted to be intolerant to loss-of-function and missense variants.

We have identified genes that are likely to increase schizophrenia risk in 3 of the 6 pedigrees examined, the strongest evidence being for a gene involved in calcium homeostasis. Further work is required to examine other classes of variants that may be contributing to disease burden.