LAUSR

An extensive catalog of common and rare genetic variants contributes to overall risk for schizophrenia and related disorders. As a complement to population genetics efforts, here we present whole genome sequences of multiple affected probands within individual families to search for possible high penetrance driver variants. From a total of 15 families diagnostically evaluated by a single research psychiatrist, we performed whole genome sequencing of a total of 61 affected individuals, called SNPs, indels, and copy number variants, and compared to reference genomes. In fourteen out of fifteen families, the schizophrenia polygenic risk score for each proband was within the control range defined by the Thousand Genomes cohort. In six families, each affected member carried a very rare or private, predicted-damaging, variant in at least one gene. Among these genes, variants in LRP1 and TENM2 suggest these are candidate disease-related genes when taken into context with existing population genetic studies and biological information. Results add to the number of pedigree sequences reported, suggest pathways for the investigation of biological mechanisms, and are consistent with the overall accumulating evidence that very rare damaging variants contribute to the heritability of schizophrenia.