title: 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.
authors.affiliation: Department of Psychiatry, Columbia University, New York, NY, USA.
authors.forename: Bin
authors.initials: B
authors.lastname: Xu
authors.forename: Iuliana
authors.initials: I
authors.lastname: Ionita-Laza
authors.forename: J Louw
authors.initials: JL
authors.lastname: Roos
authors.forename: Braden
authors.initials: B
authors.lastname: Boone
authors.forename: Scarlet
authors.initials: S
authors.lastname: Woodrick
authors.forename: Yan
authors.initials: Y
authors.lastname: Sun
authors.forename: Shawn
authors.initials: S
authors.lastname: Levy
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Gogos
authors.forename: Maria
authors.initials: M
authors.lastname: Karayiorgou
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D000328:Adult; D000071183:Autophagy-Related Proteins; D001483:Base Sequence; D001921:Brain / Q000254:growth & development; D015331:Cohort Studies; D042943:Dihydrouracil Dehydrogenase (NADP) / Q000235:genetics; D059472:Exome / Q000235:genetics; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000235:genetics; D020022:Genetic Predisposition to Disease; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D007797:Laminin / Q000235:genetics; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D009474:Neurons / Q000502:physiology*; D009687:Nuclear Proteins / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D012559:Schizophrenia / Q000235:genetics*; D017422:Sequence Analysis, DNA; D013019:South Africa; D014481:United States; D033921:Vesicular Transport Proteins / Q000235:genetics; D055815:Young Adult
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000071183:Autophagy-Related Proteins; D047908:Intracellular Signaling Peptides and Proteins; D007797:Laminin; D009687:Nuclear Proteins; C485791:VPS39 protein, human; D033921:Vesicular Transport Proteins; C102645:laminin alpha 2; C113829:transformation-transcription domain-associated protein; D042943:Dihydrouracil Dehydrogenase (NADP)