Ultrarare Missense Variants Implicated in Utah Pedigrees Multiply Affected With Schizophrenia
Cathal Ormond, Niamh Ryan, Elizabeth A. Heron, Michael Gill, William Byerley, Aiden Corvin
Abstract
Background: 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. Methods: 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. Results: is involved in intracellular calcium homeostasis, expressed in multiple brain tissue types, and predicted to be intolerant to loss-of-function and missense variants. Conclusions: 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.