Common variants conferring risk of schizophrenia

Hreinn Stefansson, Roel A. Ophoff, Stacy Steinberg, Ole A. Andreassen, Sven Cichon, Dan Rujescu, Thomas Werge, Olli P H Pietiläinen, Ole Mors, Preben B Mortensen, Engilbert Sigurdsson, Omar Gustafsson, Mette Nyegaard, Annamari Tuulio-Henriksson, Andres Ingason, Thomas Hansen, Jaana Suvisaari, Jouko Lonnqvist, Tiina Paunio, Anders D BørglumAnnette Hartmann, Anders Fink-Jensen, Merete Nordentoft, David Hougaard, Bent Norgaard-Pedersen, Yvonne Böttcher, Jes Olesen, René Breuer, Hans-Jürgen Möller, Ina Giegling, Henrik B Rasmussen, Sally Timm, Manuel Mattheisen, István Bitter, János M Réthelyi, Brynja B. Magnusdottir, Thordur Sigmundsson, Pall Olason, Gisli Masson, Jeffrey R. Gulcher, Magnus Haraldsson, Ragnheidur Fossdal, Thorgeir E. Thorgeirsson, Unnur Thorsteinsdottir, Mirella Ruggeri, Sarah Tosato, Barbara Franke, Eric Strengman, Nicholas Walker, David St Clair, Genetic Risk and Outcome in Psychosis (GROUP)

Research output: Contribution to journalLetterpeer-review

1382 Citations (Scopus)


Schizophrenia is a complex disorder, caused by both genetic and environmental factors and their interactions. Research on pathogenesis has traditionally focused on neurotransmitter systems in the brain, particularly those involving dopamine. Schizophrenia has been considered a separate disease for over a century, but in the absence of clear biological markers, diagnosis has historically been based on signs and symptoms. A fundamental message emerging from genome-wide association studies of copy number variations (CNVs) associated with the disease is that its genetic basis does not necessarily conform to classical nosological disease boundaries. Certain CNVs confer not only high relative risk of schizophrenia but also of other psychiatric disorders. The structural variations associated with schizophrenia can involve several genes and the phenotypic syndromes, or the 'genomic disorders', have not yet been characterized. Single nucleotide polymorphism (SNP)-based genome-wide association studies with the potential to implicate individual genes in complex diseases may reveal underlying biological pathways. Here we combined SNP data from several large genome-wide scans and followed up the most significant association signals. We found significant association with several markers spanning the major histocompatibility complex (MHC) region on chromosome 6p21.3-22.1, a marker located upstream of the neurogranin gene (NRGN) on 11q24.2 and a marker in intron four of transcription factor 4 (TCF4) on 18q21.2. Our findings implicating the MHC region are consistent with an immune component to schizophrenia risk, whereas the association with NRGN and TCF4 points to perturbation of pathways involved in brain development, memory and cognition.
Original languageEnglish
Pages (from-to)744-747
Number of pages4
Issue number7256
Early online date1 Jul 2009
Publication statusPublished - 6 Aug 2009


  • chromosomes, human, pair 18
  • polymorphism, single nucleotide
  • genome, human
  • DNA-binding proteins
  • humans
  • basic helix-loop-helix leucine zipper transcription factors
  • genetic markers
  • chromosomes, human, pair 6
  • chromosomes, human, pair 11
  • genome-wide association study
  • neurogranin
  • schizophrenia
  • genotype
  • transcription factors
  • genetic predisposition to disease
  • major histocompatibility complex


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