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Common schizophrenia alleles are enriched in mutation-intolerant genes and in regions under strong background selection

Research output: Contribution to journalArticle

  • Antonio F. Pardiñas
  • Peter A Holmans
  • Andrew J Pocklington
  • Valentina Escott-Price
  • Stephan Ripke
  • Noa Carrera
  • Sophie E. Legge
  • Sophie Bishop
  • Darren Cameron
  • Marian L Hamshere
  • Jun Han
  • Leon Hubbard
  • Amy Lynham
  • Kiran Mantripragada
  • Elliott Rees
  • James H MacCabe
  • Steven A. McCarroll
  • Bernhard T. Baune
  • Gerome Breen
  • Enda M Byrne
  • Udo Dannlowski
  • Thalia C Eley
  • Caroline Hayward
  • Nicholas G Martin
  • Andrew M McIntosh
  • Robert Plomin
  • David J Porteous
  • Naomi R Wray
  • Armando Caballero
  • Daniel H Geschwind
  • Laura M Huckins
  • Douglas M Ruderfer
  • Enrique Santiago
  • Pamela Sklar
  • Eli A Stahl
  • Hyejung Won
  • Esben Agerbo
  • Thomas D. Als
  • Ole A Andreassen
  • Marie Bækvad-Hansen
  • Preben Bo Mortensen
  • Carsten Bøcker Pedersen
  • Anders D Børglum
  • Jonas Bybjerg-Grauholm
  • Srdjan Djurovic
  • Naser Durmishi
  • Marianne Giørtz Pedersen
  • Vera Golimbet
  • Jakob Grove
  • David M Hougaard
  • GERAD1 Consortium:

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Original languageEnglish
JournalNature Genetics
Early online date26 Feb 2018
DOIs
Publication statusE-pub ahead of print - 26 Feb 2018

Abstract

Schizophrenia is a debilitating psychiatric condition often associated with poor quality of life and decreased life expectancy. Lack of progress in improving treatment outcomes has been attributed to limited knowledge of the underlying biology, although large-scale genomic studies have begun to provide insights. We report a new genome-wide association study of schizophrenia (11,260 cases and 24,542 controls), and through meta-analysis with existing data we identify 50 novel associated loci and 145 loci in total. Through integrating genomic fine-mapping with brain expression and chromosome conformation data, we identify candidate causal genes within 33 loci. We also show for the first time that the common variant association signal is highly enriched among genes that are under strong selective pressures. These findings provide new insights into the biology and genetic architecture of schizophrenia, highlight the importance of mutation-intolerant genes and suggest a mechanism by which common risk variants persist in the population.

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