title: DRD2 co-expression network and a related polygenic index predict imaging, behavioral and clinical phenotypes linked to schizophrenia.
abstract: Genetic risk for schizophrenia (SCZ) is determined by many genetic loci whose compound biological effects are difficult to determine. We hypothesized that co-expression pathways of SCZ risk genes are associated with system-level brain function and clinical phenotypes of SCZ. We examined genetic variants related to the dopamine D2 receptor gene DRD2 co-expression pathway and associated them with working memory (WM) behavior, the related brain activity and treatment response. Using two independent post-mortem prefrontal messenger RNA (mRNA) data sets (total N=249), we identified a DRD2 co-expression pathway enriched for SCZ risk genes. Next, we identified non-coding single-nucleotide polymorphisms (SNPs) associated with co-expression of this pathway. These SNPs were associated with regulatory genetic loci in the dorsolateral prefrontal cortex (P<0.05). We summarized their compound effect on co-expression into a Polygenic Co-expression Index (PCI), which predicted DRD2 pathway co-expression in both mRNA data sets (all P<0.05). We associated the PCI with brain activity during WM performance in two independent samples of healthy individuals (total N=368) and 29 patients with SCZ who performed the n-back task. Greater predicted DRD2 pathway prefrontal co-expression was associated with greater prefrontal activity and longer WM reaction times (all corrected P<0.05), thus indicating inefficient WM processing. Blind prediction of treatment response to antipsychotics in two independent samples of patients with SCZ suggested better clinical course of patientswith greater PCI (total N=87; P<0.05). The findings on this DRD2 co-expression pathway are a proof of concept that gene co-expression can parse SCZ risk genes into biological pathways associated with intermediate phenotypes as well as with clinically meaningful information.
authors.affiliation: Department of Basic Medical Science, Neuroscience and Sense Organs, University of Bari Aldo Moro, Bari, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Pergola
authors.affiliation: Department of Basic Medical Science, Neuroscience and Sense Organs, University of Bari Aldo Moro, Bari, Italy.
authors.forename: P
authors.initials: P
authors.lastname: Di Carlo
authors.affiliation: Department of Basic Medical Science, Neuroscience and Sense Organs, University of Bari Aldo Moro, Bari, Italy.|Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, USA.
authors.forename: E
authors.initials: E
authors.lastname: D'Ambrosio
authors.affiliation: Department of Basic Medical Science, Neuroscience and Sense Organs, University of Bari Aldo Moro, Bari, Italy.
authors.forename: B
authors.initials: B
authors.lastname: Gelao
authors.affiliation: Department of Basic Medical Science, Neuroscience and Sense Organs, University of Bari Aldo Moro, Bari, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Fazio
authors.affiliation: Department of Basic Medical Science, Neuroscience and Sense Organs, University of Bari Aldo Moro, Bari, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Papalino
authors.affiliation: Department of Basic Medical Science, Neuroscience and Sense Organs, University of Bari Aldo Moro, Bari, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Monda
authors.affiliation: Department of Basic Medical Science, Neuroscience and Sense Organs, University of Bari Aldo Moro, Bari, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Scozia
authors.affiliation: Department of Basic Medical Science, Neuroscience and Sense Organs, University of Bari Aldo Moro, Bari, Italy.
authors.forename: B
authors.initials: B
authors.lastname: Pietrangelo
authors.affiliation: Department of Basic Medical Science, Neuroscience and Sense Organs, University of Bari Aldo Moro, Bari, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Attrotto
authors.affiliation: National Institutes of Health, National Institute of Mental Health, Clinical and Translational Neuroscience Branch, NIMH, Bethesda, MD, USA.
authors.forename: J A
authors.initials: JA
authors.lastname: Apud
authors.affiliation: Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, USA.
authors.forename: Q
authors.initials: Q
authors.lastname: Chen
authors.affiliation: Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, USA.|Departments of Neurology and Radiology, Johns Hopkins School of Medicine, Baltimore, MD, USA.
authors.forename: V S
authors.initials: VS
authors.lastname: Mattay
authors.affiliation: Department of Basic Medical Science, Neuroscience and Sense Organs, University of Bari Aldo Moro, Bari, Italy.|Institute of Psychiatry, Department of Neuroscience, Sense Organs and Locomotive System, Bari University Hospital, Bari, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Rampino
authors.affiliation: Institute of Psychiatry, Department of Neuroscience, Sense Organs and Locomotive System, Bari University Hospital, Bari, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Caforio
authors.affiliation: Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, USA.|Departments of Psychiatry, Neurology, Neuroscience and The Mckusick-Nathans Institute of Genomic Medicine, Johns Hopkins School of Medicine, Baltimore, MD, USA.
authors.forename: D R
authors.initials: DR
authors.lastname: Weinberger
authors.affiliation: Institute of Psychiatry, Department of Neuroscience, Sense Organs and Locomotive System, Bari University Hospital, Bari, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Blasi
authors.affiliation: Department of Basic Medical Science, Neuroscience and Sense Organs, University of Bari Aldo Moro, Bari, Italy.|Institute of Psychiatry, Department of Neuroscience, Sense Organs and Locomotive System, Bari University Hospital, Bari, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Bertolino
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014150:Antipsychotic Agents / Q000627:therapeutic use; D001344:Autopsy; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism / Q000503:physiopathology; D002648:Child; D002675:Child, Preschool; D005260:Female; D059907:Functional Neuroimaging; D053263:Gene Regulatory Networks; D020022:Genetic Predisposition to Disease; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008279:Magnetic Resonance Imaging; D008297:Male; D008570:Memory, Short-Term; D008875:Middle Aged; D020412:Multifactorial Inheritance; D017350:N-Acetylgalactosaminyltransferases / Q000235:genetics; D000071185:Pharmacogenomic Testing; D020641:Polymorphism, Single Nucleotide; D017397:Prefrontal Cortex / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000503:physiopathology; D012333:RNA, Messenger / Q000378:metabolism*; D017448:Receptors, Dopamine D2 / Q000235:genetics*; D012097:Repressor Proteins / Q000235:genetics; D012559:Schizophrenia / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000235:genetics* / Q000503:physiopathology; D059467:Transcriptome; D055815:Young Adult; D000097763:Polypeptide N-acetylgalactosaminyltransferase
chemical_list: D014150:Antipsychotic Agents; D017350:N-Acetylgalactosaminyltransferases; D012333:RNA, Messenger; D017448:Receptors, Dopamine D2; D012097:Repressor Proteins; D000097763:Polypeptide N-acetylgalactosaminyltransferase; C581293:DRD2 protein, human; C468769:GATAD2A protein, human