Ultra-rare missense variants implicated in Utah pedigrees multiply affected with schizophrenia

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

Methods
Here we examine whole genome sequencing data from 35 individuals across six pedigrees multiply affected by schizophrenia. We applied a rigorous filtering pipeline to search for classes of protein-coding variants that co-segregated with disease status and these we examined 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.

Results
We identified deleterious missense variants in three genes (ATP2B2, SLC25A28, and GSK3A) that co-segregated with disease in three of the pedigrees. In the SCHEMA the gene ATP2B2 shows highly suggestive evidence for deleterious missense variants in schizophrenia cases (p=0.000072). ATP2B2 is involved in intracellular calcium homeostasis, is expressed in multiple brain tissue types, and is predicted to be intolerant to loss-of-function and missense variants.

Conclusions
We have identified genes that are likely increasing schizophrenia risk in three of the six pedigrees examined; the strongest evidence being for a gene involved in calcium homeostasis. Further work is required to examine other classes of variants which may be contributing to disease burden.