A polygenic burden of rare disruptive mutations in schizophrenia

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, Noboru H. Komiyama, Jyoti S. Choudhary, Patrik K. E. Magnusson, Eric Banks, Khalid ShakirKiran Garimella, Tim Fennell, Mark DePristo, Seth G. N. Grant, Stephen J. Haggarty, Stacey Gabriel, Edward M. Scolnick, Eric S. Lander, Christina M. Hultman, Patrick F. Sullivan, Steven A. McCarroll, Pamela Sklar

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)185-190
Number of pages6
JournalNature
Volume506
Issue number7487
Early online date22 Jan 2014
DOIs
Publication statusPublished - 13 Feb 2014

Keywords

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

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