title: Contrasting changes in DRD1 and DRD2 splice variant expression in schizophrenia and affective disorders, and associations with SNPs in postmortem brain.
abstract: Dopamine 2 receptor (DRD2) is of major interest to the pathophysiology of schizophrenia (SCZ) both as a target for antipsychotic drug action as well as a SCZ-associated risk gene. The dopamine 1 receptor (DRD1) is thought to mediate some of the cognitive deficits in SCZ, including impairment of working memory that relies on normal dorsolateral prefrontal cortex (DLPFC) function. To better understand the association of dopamine receptors with SCZ, we studied the expression of three DRD2 splice variants and the DRD1 transcript in DLPFC, hippocampus and caudate nucleus in a large cohort of subjects (~700), including patients with SCZ, affective disorders and nonpsychiatric controls (from 14th gestational week to 85 years of age), and examined genotype-expression associations of 278 single-nucleotide polymorphisms (SNPs) located in or near DRD2 and DRD1 genes. Expression of D2S mRNA and D2S/D2-long (D2L) ratio were significantly increased in DLPFC of patients with SCZ relative to controls (P<0.0001 and P<0.0001, respectively), whereas D2L, D2Longer and DRD1 were decreased (P<0.0001). Patients with affective disorders showed an opposite pattern: reduced expression of D2S (major depressive disorder, P<0.0001) and increased expression of D2L and DRD1 (bipolar disorder, P<0.0001). Moreover, SCZ-associated risk alleles at rs1079727, rs1076560 and rs2283265 predicted increased D2S/D2L expression ratio (P<0.05) in control individuals. Our data suggest that altered splicing of DRD2 and expression of DRD1 may constitute a pathophysiological mechanism in risk for SCZ and affective disorders. The association between SCZ risk-associated polymorphism and the ratio of D2S/D2L is consistent with this possibility.
authors: 1] Human Brain Collection Core, IRP, National Institute of Mental Health, Bethesda, MD, USA [2] Research Laboratory for Stereology and Neuroscience, Bispebjerg University Hospital, Copenhagen NV, Denmark [3]  Faculty of Health Sciences, Protein Laboratory, Institute of Neuroscience and Pharmacology, University of Copenhagen, Copenhagen, Denmark.
authors: S S
authors: SS
authors: Kaalund
authors: Human Brain Collection Core, IRP, National Institute of Mental Health, Bethesda, MD, USA.
authors: E N
authors: EN
authors: Newburn
authors: Lieber Institute for Brain Development, Baltimore, MD, USA.
authors: T
authors: T
authors: Ye
authors: Lieber Institute for Brain Development, Baltimore, MD, USA.
authors: R
authors: R
authors: Tao
authors: Lieber Institute for Brain Development, Baltimore, MD, USA.
authors: C
authors: C
authors: Li
authors: Lieber Institute for Brain Development, Baltimore, MD, USA.
authors: A
authors: A
authors: Deep-Soboslay
authors: Human Brain Collection Core, IRP, National Institute of Mental Health, Bethesda, MD, USA.
authors: M M
authors: MM
authors: Herman
authors: Lieber Institute for Brain Development, Baltimore, MD, USA.
authors: T M
authors: TM
authors: Hyde
authors: Lieber Institute for Brain Development, Baltimore, MD, USA.
authors: D R
authors: DR
authors: Weinberger
authors: Human Brain Collection Core, IRP, National Institute of Mental Health, Bethesda, MD, USA.
authors: B K
authors: BK
authors: Lipska
authors: Lieber Institute for Brain Development, Baltimore, MD, USA.
authors: J E
authors: JE
authors: Kleinman
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001714:Bipolar Disorder / Q000235:genetics* / Q000378:metabolism; D001921:Brain / Q000254:growth & development / Q000378:metabolism*; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D003865:Major Depressive Disorder / Q000235:genetics* / Q000378:metabolism; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D012326:RNA Splicing; D012333:RNA, Messenger / Q000378:metabolism; D017447:Receptors, Dopamine D1 / Q000235:genetics* / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000235:genetics* / Q000378:metabolism; D012559:Schizophrenia / Q000235:genetics* / Q000378:metabolism; D055815:Young Adult
chemical_list: C583260:DRD1 protein, human; C581293:DRD2 protein, human; D012333:RNA, Messenger; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2