title: Prefrontal inefficiency is associated with polygenic risk for schizophrenia.
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.
authors: Department of Child and Adolescent Psychiatry, University Hospital Carl Gustav Carus, Dresden University of Technology, Dresden, Germany;
authors: Esther
authors: E
authors: Walton
authors: Department of Child and Adolescent Psychiatry, University Hospital Carl Gustav Carus, Dresden University of Technology, Dresden, Germany;
authors: Daniel
authors: D
authors: Geisler
authors: Phil H
authors: PH
authors: Lee
authors: Department of Child and Adolescent Psychiatry, University Hospital Carl Gustav Carus, Dresden University of Technology, Dresden, Germany;
authors: Johanna
authors: J
authors: Hass
authors: The Mind Research Network, Albuquerque, NM;
authors: Jessica A
authors: JA
authors: Turner
authors: The Mind Research Network, Albuquerque, NM;
authors: Jingyu
authors: J
authors: Liu
authors: Minneapolis Veterans Affairs Health Care System, Minneapolis, MN; Department of Psychiatry, University of Minnesota, Minneapolis, MN;
authors: Scott R
authors: SR
authors: Sponheim
authors: Department of Child and Adolescent Psychiatry, Erasmus University, Rotterdam, Netherlands;
authors: Tonya
authors: T
authors: White
authors: Department of Psychiatry, University of Iowa, Iowa City, IA;
authors: Thomas H
authors: TH
authors: Wassink
authors: Department of Child and Adolescent Psychiatry, University Hospital Carl Gustav Carus, Dresden University of Technology, Dresden, Germany;
authors: Veit
authors: V
authors: Roessner
authors: Department of Psychiatry, Massachusetts General Hospital/Harvard Medical School, Boston, MA; MGH/MIT/HMS Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Charlestown, MA;
authors: Randy L
authors: RL
authors: Gollub
authors: The Mind Research Network, Albuquerque, NM; Department of Electrical and Computer Engineering, University of New Mexico, Albuquerque, NM.
authors: Vince D
authors: VD
authors: Calhoun
authors: Department of Child and Adolescent Psychiatry, University Hospital Carl Gustav Carus, Dresden University of Technology, Dresden, Germany; Department of Psychiatry, Massachusetts General Hospital/Harvard Medical School, Boston, MA; MGH/MIT/HMS Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Charlestown, MA; stefan@nmr.mgh.harvard.edu.
authors: Stefan
authors: S
authors: Ehrlich
mesh_terms: D000328:Adult; D016022:Case-Control Studies; D005260:Female; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008570:Memory, Short-Term / Q000502:physiology; D008875:Middle Aged; D020412:Multifactorial Inheritance; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D017397:Prefrontal Cortex / Q000503:physiopathology*; D012306:Risk; D012559:Schizophrenia / Q000235:genetics* / Q000503:physiopathology*
keywords: DLPFC; fMRI; genetic risk score; intermediate phenotype; schizophrenia; working memory