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Nature DOI:10.1038/nature12929

De novo mutations in schizophrenia implicate synaptic networks.

Publication TypeJournal Article
Year of Publication2014
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, O'Donovan, MC
Date Published2014 Feb 13
KeywordsChild Development Disorders, Pervasive, Cytoskeletal Proteins, Exome, Fragile X Mental Retardation Protein, Humans, Intellectual Disability, Models, Neurological, Mutation, Mutation Rate, Nerve Net, Nerve Tissue Proteins, Neural Pathways, Phenotype, Receptors, N-Methyl-D-Aspartate, RNA, Messenger, Schizophrenia, Substrate Specificity, Synapses

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.


Alternate JournalNature
PubMed ID24463507
PubMed Central IDPMC4237002
Grant List2 P50MH066392-05A1 / MH / NIMH NIH HHS / United States
R01 MH071681 / MH / NIMH NIH HHS / United States
R01MH071681 / MH / NIMH NIH HHS / United States
098051 / / Wellcome Trust / United Kingdom
R01 MH099126 / MH / NIMH NIH HHS / United States
I01 BX002395 / BX / BLRD VA / United States
089062 / / Wellcome Trust / United Kingdom
R01HG005827 / HG / NHGRI NIH HHS / United States
R01 HG005827 / HG / NHGRI NIH HHS / United States
G0801418 / / Medical Research Council / United Kingdom
MR/L010305/1 / / Medical Research Council / United Kingdom
G0800509 / / Medical Research Council / United Kingdom
R01MH099126 / MH / NIMH NIH HHS / United States