De novo mutations in schizophrenia implicate synaptic networks

Abstract

Summary Inherited alleles account for most of the genetic risk for schizophrenia. However, new (de novo) mutations, in the form of large chromosomal copy number changes, occur in a small fraction of cases and disproportionally disrupt genes encoding postsynaptic proteins. Here, we show that small de novo mutations, affecting one or a few nucleotides, are overrepresented among glutamatergic postsynaptic proteins comprising activity-regulated cytoskeleton-associated protein (ARC) and N-methyl-D-aspartate receptor (NMDAR) complexes. Mutations are additionally enriched in proteins that interact with these complexes to modulate synaptic strength, namely proteins regulating actin filament dynamics and those whose mRNAs are targets of fragile X mental retardation protein (FMRP). Genes affected by mutations in schizophrenia overlap those mutated in autism and intellectual disability, as do mutation-enriched synaptic pathways. Aligning our findings with a parallel case-control study, we demonstrate reproducible insights into aetiological mechanisms for schizophrenia and reveal pathophysiology shared with other neurodevelopmental disorders.

10 Years of GWAS Discovery: Biology, Function, and Translation

“…26 However, genetic architecture, described as the mix of rare and common variants, is likely to differ between psychiatric disorders, as is already being observed for the higher rates of rare, de novo penetrant CNVs and single-nucleotide variants found in autism than in schizophrenia or bipolar disorder. [121][122][123][124][125][126][127][128][129] PRS studies are being utilized extensively to investigate disease heterogeneity and contributions from environmental risk factors.…”

Dendritic spine actin cytoskeleton in autism spectrum disorder

“…IRSp53 has been implicated also in other psychiatric disorders, including ADHD (attention deficit/hyperactivity disorder) 207,208 and schizophrenia 209,210 . Overexpression of IRSp53 in cultured neurons increases the density of dendritic spines without affecting spine length or width.…”

No evidence for rare recessive and compound heterozygous disruptive variants in schizophrenia

“…10 To focus on rare variants that are a priori more likely to be highly penetrant for disease, one approach is to study de novo mutations, as these are effectively uncensored by selection pressures. 11 A second strategy, adopted here, is to focus on the rare gene-disruptive variants, defined as nonsense, essential splice site or frameshift, where both copies of a gene are affected through homozygosity at a single site or compound heterozygosity (if an individual carries different disruptive variants on both the maternally and paternally derived copies of the gene). With respect to any one gene, we refer to these as 'complete knockout' variants.…”