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 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.

Genetic studies of schizophrenia: an update

“…This hypothesis did not receive much attention in genetic studies until recently, when high-throughput DNA sequencing of SCZ families provided direct evidence that affected offspring have excess DNMs across the genome [72,73] . Further studies of DNMs in individual genes [74,75] , a particular set of genes [76,77] , or the exome [78][79][80] , also provided evidence that DNMs are enriched in SCZ patients. Direct measurement also indicates that SCZ patients have a higher mutation rate [76] .…”

“…It should be pointed out that DNMs can be CNVs [48,81] , Detailed analyses of DNMs in affected offspring reveal an excess of missense and disrupting mutations in proteincoding sequences, especially those involved in synaptic functions [77,79] . While most DNMs are unique events, some are recurrent [79] .…”

“…While most DNMs are unique events, some are recurrent [79] . Analyses of rare mutations reach the same conclusion that the polygenic burden of rare disruptive mutations is excessive in SCZ patients [80] .…”

Advancing paternal age at birth is associated with poorer social functioning earlier and later in life of schizophrenia patients in a founder population

“…In addition to the genetic homogeneity, the Afrikaners are valuable for genetic studies because they present a close-knit family structure and offer the potential to perform detailed genealogical analysis, which affords reliable discrimination of familial and non-familial (sporadic) forms of the disease (Xu et al, 2012). We identified and extracted the sporadic cohort (i.e.…”

Phelan‐McDermid syndrome data network: Integrating patient reported outcomes with clinical notes and curated genetic reports

“…Research investigations using Genome Wide Association Study (GWAS) (Network and Pathway Analysis Subgroup of the Psychiatric Genomics Consortium, 2015; Wood, 2013), exome‐based sequencing (Girard et al, 2011; Iossifov et al, 2012; O'Roak et al, 2011; Vissers et al, 2010; Xu et al, 2012), and whole genome sequencing (Kong et al, 2012) techniques have revealed several candidate genes that are associated with common neuropsychiatric disorders such as Autism Spectrum Disorder (ASD), intellectual disability, and schizophrenia. However, in the case of rare disorders, understanding the genetic origins and progressions of disorders—one of the key objectives of Precision Medicine research (Collins & Varmus, 2015; Kohane, 2015; Kohane, Churchill, & Murphy, 2012)—is hindered by small patient population size, the consequent paucity of patient data, and the lack of robust phenotyping protocols (Baynam et al, 2015; Delude, 2015; Robinson, Mungall, & Haendel, 2015).…”