Scientific Publications

De novo mutations in schizophrenia implicate synaptic networks.

Publication TypeJournal Article
AuthorsFromer, M., Pocklington AJ, Kavanagh DH, Williams HJ, Dwyer S., Gormley P., Georgieva L., Rees E., Palta P., Ruderfer DM, Carrera N., Humphreys I., Johnson JS, Roussos P., Barker DD, Banks E., Milanova V., Grant SG, Hannon E., Rose SA, Chambert K., Mahajan M., Scolnick EM, Moran JL, Kirov G., Palotie A., McCarroll SA, Holmans P., Sklar P., Owen MJ, Purcell SM, and O'Donovan MC
AbstractInherited 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.
Year of Publication2014
JournalNature
Volume506
Issue7487
Pages179-84
Date Published (YYYY/MM/DD)2014/02/13
ISSN Number0028-0836
DOI10.1038/nature12929
PubMedhttp://www.ncbi.nlm.nih.gov/pubmed/24463507?dopt=Abstract