Prefrontal inefficiency is associated with polygenic risk for schizophrenia

Esther Walton, Daniel Geisler, Phil H Lee, Johanna Hass, Jessica A Turner, Jingyu Liu, Scott R Sponheim, Tonya White, Thomas H Wassink, Veit Roessner, Randy L Gollub, Vince D Calhoun, Stefan Ehrlich

Research output: Contribution to journalArticle (Academic Journal)

36 Citations (Scopus)

Abstract

Considering the diverse clinical presentation and likely polygenic etiology of schizophrenia, this investigation examined the effect of polygenic risk on a well-established intermediate phenotype for schizophrenia. We hypothesized that a measure of cumulative genetic risk based on additive effects of many genetic susceptibility loci for schizophrenia would predict prefrontal cortical inefficiency during working memory, a brain-based biomarker for the disorder. The present study combined imaging, genetic and behavioral data obtained by the Mind Clinical Imaging Consortium study of schizophrenia (n = 255). For each participant, we derived a polygenic risk score (PGRS), which was based on over 600 nominally significant single nucleotide polymorphisms, associated with schizophrenia in a separate discovery sample comprising 3322 schizophrenia patients and 3587 control participants. Increased polygenic risk for schizophrenia was associated with neural inefficiency in the left dorsolateral prefrontal cortex after covarying for the effects of acquisition site, diagnosis, and population stratification. We also provide additional supporting evidence for our original findings using scores based on results from the Psychiatric Genomics Consortium study. Gene ontology analysis of the PGRS highlighted genetic loci involved in brain development and several other processes possibly contributing to disease etiology. Our study permits new insights into the additive effect of hundreds of genetic susceptibility loci on a brain-based intermediate phenotype for schizophrenia. The combined impact of many common genetic variants of small effect are likely to better reveal etiologic mechanisms of the disorder than the study of single common genetic variants.

Original languageEnglish
Pages (from-to)1263-71
Number of pages9
JournalSchizophrenia Bulletin
Volume40
Issue number6
DOIs
Publication statusPublished - Nov 2014

Keywords

  • Adult
  • Case-Control Studies
  • Female
  • Humans
  • Magnetic Resonance Imaging
  • Male
  • Memory, Short-Term
  • Middle Aged
  • Multifactorial Inheritance
  • Phenotype
  • Polymorphism, Single Nucleotide
  • Prefrontal Cortex
  • Risk
  • Schizophrenia

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