De novo mutations in schizophrenia implicate synaptic networks

By Menachem Fromer, A. Pocklington, D. Kavanagh, H. Williams, S. Dwyer, P. Gormley, L. Georgieva, E. Rees, P. Palta, D. Ruderfer and 22 more. 2014

1,622 citations recorded by the source corpus.

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 messenger RNAs 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.

Subfields: Genetics, Molecular Biology

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Citations in the corpus

Gene Expression Elucidates Functional Impact of Polygenic Risk for Schizophrenia (2016, background): “The 109 available data are incomplete but implicate synaptic components, including calcium channel 110 subunits and post-synaptic elements (5, 7-9).”
A SPECTRAL APPROACH INTEGRATING FUNCTIONAL GENOMIC ANNOTATIONS FOR CODING AND NONCODING VARIANTS (2016, background): “For SCZ, we have n =636 mutations of which 571 are missense [27, 28, 29, 30, 31].”
Research review: Polygenic methods and their application to psychiatric traits. (2014, methodology): “Therefore, other methods have been developed that analyse all SNPs simultaneously, first for quantitative traits (Fernando, 1998; Goddard, 2009; Habier, Fernando, & Dekkers, 2007; VanRaden, 2008; Yang et al., 2010), and later extended to disease traits (Lee, Wray, Goddard, & Visscher, 2011).”
Biological Psychology : Stress (2016, positive): “Analyses of de novo copy number variations also implicate NMDA receptors, with enrichment of nonsynonymous polymorphisms and loss of function mutations in the GRIN2A gene in individuals with schizophrenia (Fromer et al., 2014; Kirov et al., 2012).”