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

Abstract

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 structures 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 de novo nonsynonymous single-nucleotide variants as well as a higher prevalence of gene-disruptive de novo mutations relative to controls. We found four genes (LAMA2, DPYD, TRRAP and VPS39) affected by recurrent de novo events within or across the two populations, which is 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 genomic and neural architecture of schizophrenia.

Figure 1. Enrichment of non-syn or functional de novo variants according to temporal expression profiles of targets genes

a. We grouped our target genes from the combined schizophrenia cohorts into three classes [prenatal brain expression biased (“prenatally-biased”), postnatal brain expression biased (“postnatally-biased”) and “non-biased”] according to their temporal trajectory in reference to a previously described global expression switch occurring before birth and determined the relative enrichment of non-syn or, more generally, functional de novo variants over syn ones. The relative enrichment in differentially regulated target genes is shown for de novo mutations in the Afrikaner and US probands (top) and the combined SSC control group (middle), as well as for private transmitted variants in Afrikaner and US probands (bottom). The non-syn/syn ratio for prenatally-biased genes was significantly higher than neutral expectation (2.23) (7, P = 0.004). In comparison, the corresponding values for postnatally-biased genes were 4.4 (P = 0.06), whereas for non-biased genes were 4.13 (P = 0.12). Similar analysis of de novo variants in the SSC control group or of private transmitted variants in Afrikaner and US probands showed no differential in the distribution of effect sizes in any of the temporal trajectories tested. ‘Non-syn’ refers to non-synonymous mutations (missense and nonsense SNVs); “functional” refers to non-syn, indel and splice site mutations. Indel data was not available for transmitted variants. b. Left: An elevated frequency of patients who had multiple (≥ 3) childhood behavioral abnormalities (Supplementary Note) was found among carriers of de novo functional mutations in prenatally-biased genes (10 out of 29 compared to 4 out of 51 patients carrying mutations in genes with no fetal brain bias, 4.4-fold enrichment, P = 0.0047, Fisher’s exact test). Right: An elevated frequency of patients with severe disease functional outcome (Supplementary Note) was found among carriers of de novo functional mutations in prenatally-biased genes (35 out of 38 compared to 45 out of 66 patients carrying mutations in genes with no fetal brain bias, 1.35-fold enrichment, P = 0.007, Fisher’s exact test). c. Venn diagrams depicting the overlap between either all target genes or only prenatally-biased genes harboring functional de novo mutations identified in the Afrikaner and US probands (n = 145) and those identified in ASD exome scans^- (n = 675).