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De novo mutations in schizophrenia implicate synaptic networks

Research output: Contribution to journalArticle

  • Menachem Fromer
  • Andrew J. Pocklington
  • David H. Kavanagh
  • Hywel J. Williams
  • Sarah Dwyer
  • Padhraig Gormley
  • Lyudmila Georgieva
  • Elliott Rees
  • Priit Palta
  • Douglas M. Ruderfer
  • Noa Carrera
  • Isla Humphreys
  • Jessica S. Johnson
  • Panos Roussos
  • Douglas D. Barker
  • Eric Banks
  • Vihra Milanova
  • Eilis Hannon
  • Samuel A. Rose
  • Kimberly Chambert
  • Milind Mahajan
  • Edward M. Scolnick
  • Jennifer L. Moran
  • George Kirov
  • Aarno Palotie
  • Steven A. McCarroll
  • Peter Holmans
  • Pamela Sklar
  • Michael J. Owen
  • Shaun M. Purcell
  • Michael C. O'Donovan

Related Edinburgh Organisations

Original languageEnglish
Pages (from-to)179-+
Number of pages16
JournalNature
Volume506
Issue number7487
DOIs
Publication statusPublished - 13 Feb 2014

Abstract

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 ora 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.

    Research areas

  • AUTISM SPECTRUM DISORDERS, COPY-NUMBER VARIANTS, INTELLECTUAL DISABILITY, DISEASE, GENE, PLASTICITY, MECHANISMS, COMPLEXITY, PATTERNS, RATES

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