De novo gene mutations highlight patterns of genetic and neural complexity in schizophrenia

To evaluate evidence for de novo etiologies in schizophrenia, we sequenced at high coverage the exomes of families recruited from two populations with distinct demographic structure and history. We sequenced a total of 795 exomes from 231 parent-proband trios enriched for sporadic schizophrenia cases, as well as 34 unaffected trios. We observed in cases an excess of non-synonymous single nucleotide variants as well as a higher prevalence of gene-disruptive de novo mutations. We found four genes (LAMA2, DPYD, TRRAP and VPS39) affected by recurrent de novo events within or across the two populations, a finding unlikely to have occurred by chance. We show that de novo mutations affect genes with diverse functions and developmental profiles but we also find a substantial contribution of mutations in genes with higher expression in early fetal life. Our results help define the pattern of genomic and neural architecture of schizophrenia.