Common variants conferring risk of schizophrenia

Nature. 2009 Aug 6;460(7256):744-7. doi: 10.1038/nature08186. Epub 2009 Jul 1.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
  • Chromosomes, Human, Pair 11 / genetics
  • Chromosomes, Human, Pair 18 / genetics
  • Chromosomes, Human, Pair 6 / genetics
  • DNA-Binding Proteins / genetics
  • Genetic Markers / genetics
  • Genetic Predisposition to Disease / genetics*
  • Genome, Human / genetics
  • Genome-Wide Association Study
  • Genotype
  • Humans
  • Major Histocompatibility Complex / genetics
  • Neurogranin / genetics
  • Polymorphism, Single Nucleotide / genetics*
  • Schizophrenia / genetics*
  • Schizophrenia / immunology
  • Transcription Factor 4
  • Transcription Factors / genetics

Substances

  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
  • DNA-Binding Proteins
  • Genetic Markers
  • NRGN protein, human
  • TCF4 protein, human
  • Transcription Factor 4
  • Transcription Factors
  • Neurogranin