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A polygenic burden of rare disruptive mutations in schizophrenia

Research output: Contribution to journalArticle

  • Shaun M. Purcell
  • Jennifer L. Moran
  • Menachem Fromer
  • Douglas Ruderfer
  • Nadia Solovieff
  • Panos Roussos
  • Colm O'Dushlaine
  • Kimberly Chambert
  • Sarah E. Bergen
  • Anna Kahler
  • Laramie Duncan
  • Eli Stahl
  • Giulio Genovese
  • Esperanza Fernandez
  • Mark O. Collins
  • Jyoti S. Choudhary
  • Patrik K. E. Magnusson
  • Eric Banks
  • Khalid Shakir
  • Kiran Garimella
  • Tim Fennell
  • Mark DePristo
  • Stephen J. Haggarty
  • Stacey Gabriel
  • Edward M. Scolnick
  • Eric S. Lander
  • Christina M. Hultman
  • Patrick F. Sullivan
  • Steven A. McCarroll
  • Pamela Sklar

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Original languageEnglish
Pages (from-to)185-+
Number of pages17
JournalNature
Volume506
Issue number7487
DOIs
Publication statusPublished - 13 Feb 2014

Abstract

Schizophrenia is a common disease with a complex aetiology, probably involving multiple and heterogeneous genetic factors. Here, by analysing the exome sequences of 2,536 schizophrenia cases and 2,543 controls, we demonstrate a polygenic burden primarily arising from rare (less than 1 in 10,000), disruptive mutations distributed across many genes. Particularly enriched gene sets include the voltage-gated calcium ion channel and the signalling complex formed by the activity-regulated cytoskeleton-associated scaffold protein (ARC) of the postsynaptic density, sets previously implicated by genome-wide association and copy-number variation studies. Similar to reports in autism, targets of the fragile X mental retardation protein (FMRP, product of FMR1) are enriched for case mutations. No individual gene-based test achieves significance after correction for multiple testing and we do not detect any alleles of moderately low frequency (approximately 0.5 to 1 per cent) and moderately large effect. Taken together, these data suggest that population-based exome sequencing can discover risk alleles and complements established gene-mapping paradigms in neuropsychiatric disease.

    Research areas

  • DE-NOVO MUTATIONS, INTELLECTUAL DISABILITY, MESSENGER-RNA, POSTSYNAPTIC DENSITY-95, PSYCHIATRIC-DISORDERS, ASSOCIATION ANALYSIS, SEQUENCING DATA, NMDA RECEPTOR, RISK LOCI, AUTISM

ID: 14284761