Rare germline mutations in individuals diagnosed with schizophrenia within multiplex families

Despite the high heritability of schizophrenia, extensive genome-wide association studies generally have not found individual variants or genes that might in of themselves predispose strongly to schizophrenia. To search directly for candidate high-penetrance variants, we executed whole-genome sequencing of families with high prevalence of schizophrenia under the hypothesis that such families might be more likely to have a high penetrance genetic cause of disease common to all affected members. From a total of 15 families diagnostically evaluated by a single research psychiatrist, we sequenced a total of 61 individuals and called SNPs and indels in coding and regulatory regions plus copy number variants. The polygenic risk score for each proband was within the control range defined by the Thousand Genomes cohort. We found six families in which each of the affected members carried a very rare or private, predicted-damaging, variant in at least one gene. Among these genes, LRP1, CAMKK2, TENM3, RELN, ATP2B2, and MAPK8IP3 have both a link to neuronal function and to human CNS disease. Results overall are consistent with the hypothesis that very rare damaging variants may contribute to the heritability of schizophrenia and may provide substrate for investigations of biological mechanisms or therapeutic targets.