What is the impact of genome-wide supported risk variants for schizophrenia and bipolar disorder on brain structure and function? A systematic review

Psychol Med. 2015;45(12):2461-80. doi: 10.1017/S0033291715000537. Epub 2015 Apr 10.


The powerful genome-wide association studies (GWAS) revealed common mutations that increase susceptibility for schizophrenia (SZ) and bipolar disorder (BD), but the vast majority were not known to be functional or associated with these illnesses. To help fill this gap, their impact on human brain structure and function has been examined. We systematically discuss this output to facilitate its timely integration in the psychosis research field; and encourage reflection for future research. Irrespective of imaging modality, studies addressing the effect of SZ/BD GWAS risk genes (ANK3, CACNA1C, MHC, TCF4, NRGN, DGKH, PBRM1, NCAN and ZNF804A) were included. Most GWAS risk variations were reported to affect neuroimaging phenotypes implicated in SZ/BD: white-matter integrity (ANK3 and ZNF804A), volume (CACNA1C and ZNF804A) and density (ZNF804A); grey-matter (CACNA1C, NRGN, TCF4 and ZNF804A) and ventricular (TCF4) volume; cortical folding (NCAN) and thickness (ZNF804A); regional activation during executive tasks (ANK3, CACNA1C, DGKH, NRGN and ZNF804A) and functional connectivity during executive tasks (CACNA1C and ZNF804A), facial affect recognition (CACNA1C and ZNF804A) and theory-of-mind (ZNF804A); but inconsistencies and non-replications also exist. Further efforts such as standardizing reporting and exploring complementary designs, are warranted to test the reproducibility of these early findings.

Keywords: ANK3; CACNA1C; DGKH; DTI; MRI; NCAN; NRGN; TCF4; ZNF804A; bipolar disorder; genome-wide association; imaging genetics; intermediate phenotypes; neuroimaging; psychosis; review; schizophrenia.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review
  • Systematic Review

MeSH terms

  • Ankyrins / genetics
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / genetics
  • Bipolar Disorder / genetics*
  • Bipolar Disorder / physiopathology*
  • Bipolar Disorder / psychology
  • Brain / physiopathology*
  • Calcium Channels, L-Type / genetics
  • Chondroitin Sulfate Proteoglycans / genetics
  • Female
  • Functional Neuroimaging
  • Genes
  • Genetic Predisposition to Disease* / genetics
  • Genetic Predisposition to Disease* / psychology
  • Genome
  • Genome-Wide Association Study
  • Humans
  • Kruppel-Like Transcription Factors / genetics
  • Lectins, C-Type / genetics
  • Male
  • Mutation / genetics
  • Nerve Tissue Proteins / genetics
  • Neurogranin / genetics
  • Phenotype
  • Polymorphism, Genetic
  • Psychotic Disorders / physiopathology
  • Risk Factors
  • Schizophrenia / genetics*
  • Schizophrenia / physiopathology*
  • Schizophrenic Psychology
  • Transcription Factor 4
  • Transcription Factors / genetics


  • ANK3 protein, human
  • Ankyrins
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
  • CACNA1C protein, human
  • Calcium Channels, L-Type
  • Chondroitin Sulfate Proteoglycans
  • Kruppel-Like Transcription Factors
  • Lectins, C-Type
  • NRGN protein, human
  • Nerve Tissue Proteins
  • TCF4 protein, human
  • Transcription Factor 4
  • Transcription Factors
  • ZNF804A protein, human
  • Neurogranin
  • NCAN protein, human