Cumulative genetic risk and prefrontal activity in patients with schizophrenia

Esther Walton, Jessica Turner, Randy L Gollub, Dara S Manoach, Anastasia Yendiki, Beng-Choon Ho, Scott R Sponheim, Vince D Calhoun, Stefan Ehrlich

Research output: Contribution to journalArticle

45 Citations (Scopus)

Abstract

The lack of consistency of genetic associations in highly heritable mental illnesses, such as schizophrenia, remains a challenge in molecular psychiatry. Because clinical phenotypes for psychiatric disorders are often ill defined, considerable effort has been made to relate genetic polymorphisms to underlying physiological aspects of schizophrenia (so called intermediate phenotypes), that may be more reliable. Given the polygenic etiology of schizophrenia, the aim of this work was to form a measure of cumulative genetic risk and study its effect on neural activity during working memory (WM) using functional magnetic resonance imaging. Neural activity during the Sternberg Item Recognition Paradigm was measured in 79 schizophrenia patients and 99 healthy controls. Participants were genotyped, and a genetic risk score (GRS), which combined the additive effects of 41 single-nucleotide polymorphisms (SNPs) from 34 risk genes for schizophrenia, was calculated. These risk SNPs were chosen according to the continuously updated meta-analysis of genetic studies on schizophrenia available at www.schizophreniaresearchforum.org. We found a positive relationship between GRS and left dorsolateral prefrontal cortex inefficiency during WM processing. GRS was not correlated with age, performance, intelligence, or medication effects and did not differ between acquisition sites, gender, or diagnostic groups. Our study suggests that cumulative genetic risk, combining the impact of many genes with small effects, is associated with a known brain-based intermediate phenotype for schizophrenia. The GRS approach could provide an advantage over studying single genes in studies focusing on the genetic basis of polygenic conditions such as neuropsychiatric disorders.
Original languageEnglish
Pages (from-to)703-711
Number of pages9
JournalSchizophrenia Bulletin
Volume39
Issue number3
DOIs
Publication statusPublished - May 2013

Keywords

  • Adult
  • Case-Control Studies
  • Female
  • Functional Neuroimaging
  • Genetic Association Studies
  • Genetic Predisposition to Disease
  • Humans
  • Image Processing, Computer-Assisted
  • Magnetic Resonance Imaging
  • Male
  • Memory, Short-Term
  • Middle Aged
  • Polymorphism, Single Nucleotide
  • Prefrontal Cortex
  • Schizophrenia
  • Young Adult

Cite this

Walton, E., Turner, J., Gollub, R. L., Manoach, D. S., Yendiki, A., Ho, B-C., Sponheim, S. R., Calhoun, V. D., & Ehrlich, S. (2013). Cumulative genetic risk and prefrontal activity in patients with schizophrenia. Schizophrenia Bulletin, 39(3), 703-711. https://doi.org/10.1093/schbul/sbr190