title: Preliminary evidence that negative symptom severity relates to multilocus genetic profile for dopamine signaling capacity and D2 receptor binding in healthy controls and in schizophrenia.
abstract: Deficits in central, subcortical dopamine (DA) signaling may underlie negative symptom severity, particularly anhedonia, in healthy individuals and in schizophrenia. To investigate these relationships, we assessed negative symptoms with the Schedule for the Assessment of Negative Symptoms and the Brief Negative Symptom Scale (BNSS) and self-reported anhedonia with the Scales for Physical and Social Anhedonia (SPSA), Temporal Experience of Pleasure Scale, and Snaith-Hamilton Pleasure Scale in 36 healthy controls (HC), 27 siblings (SIB) of individuals with schizophrenia, and 66 individuals with schizophrenia or schizoaffective disorder (SCZ). A subset of participants (N = 124) were genotyped for DA-related polymorphisms in genes for DRD4, DRD2/ANKK1, DAT1, and COMT, which were used to construct biologically-informed multi-locus genetic profile (MGP) scores reflective of subcortical dopaminergic signaling. DA receptor type 2 (D2R) binding was assessed among a second subset of participants (N = 23) using PET scans with the D2R-selective, non-displaceable radioligand (N-[11C]methyl)benperidol. Higher MGP scores, reflecting elevated subcortical dopaminergic signaling capacity, were associated with less negative symptom severity, as measured by the BNSS, across all participants. In addition, higher striatal D2R binding was associated with less physical and social anhedonia, as measured by the SPSA, across HC, SIB, and SCZ. The current preliminary findings support the hypothesis that subcortical DA function may contribute to negative symptom severity and self-reported anhedonia, independent of diagnostic status.
authors.affiliation: Psychiatry Department, Washington University School of Medicine, St. Louis, MO, USA; Radiology Department, Washington University School of Medicine, St. Louis, MO, USA. Electronic address: seisens@wustl.edu.
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Eisenstein
authors.affiliation: Psychological & Brain Sciences Department, Washington University in St. Louis, St. Louis, MO, USA. Electronic address: rbogdan@wustl.edu.
authors.forename: Ryan
authors.initials: R
authors.lastname: Bogdan
authors.affiliation: Division of Biostatistics, Washington University School of Medicine, St. Louis, MO, USA. Electronic address: lingchen@wustl.edu.
authors.forename: Ling
authors.initials: L
authors.lastname: Chen
authors.affiliation: Radiology Department, Washington University School of Medicine, St. Louis, MO, USA; Biochemistry Department, Washington University School of Medicine, St. Louis, MO, USA. Electronic address: moerleins@mir.wustl.edu.
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Moerlein
authors.affiliation: Psychiatry Department, Washington University School of Medicine, St. Louis, MO, USA; Radiology Department, Washington University School of Medicine, St. Louis, MO, USA; Neurology Department, Washington University School of Medicine, St. Louis, MO, USA; Neuroscience Department, Washington University School of Medicine, MO, USA. Electronic address: kevin@wustl.edu.
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Black
authors.affiliation: Radiology Department, Washington University School of Medicine, St. Louis, MO, USA; Biochemistry Department, Washington University School of Medicine, St. Louis, MO, USA; Programs in Physical Therapy and Occupational Therapy, Washington University School of Medicine, St. Louis, MO, USA. Electronic address: joel@wustl.edu.
authors.forename: Joel S
authors.initials: JS
authors.lastname: Perlmutter
authors.affiliation: Psychiatry Department, Washington University School of Medicine, St. Louis, MO, USA; Radiology Department, Washington University School of Medicine, St. Louis, MO, USA; Psychological & Brain Sciences Department, Washington University in St. Louis, St. Louis, MO, USA; Neurology Department, Washington University School of Medicine, St. Louis, MO, USA. Electronic address: tammy@wustl.edu.
authors.forename: Tamara
authors.initials: T
authors.lastname: Hershey
authors.affiliation: Psychiatry Department, Washington University School of Medicine, St. Louis, MO, USA; Radiology Department, Washington University School of Medicine, St. Louis, MO, USA; Psychological & Brain Sciences Department, Washington University in St. Louis, St. Louis, MO, USA. Electronic address: dbarch@wustl.edu.
authors.forename: Deanna M
authors.initials: DM
authors.lastname: Barch
mesh_terms: D000293:Adolescent; D000328:Adult; D059445:Anhedonia / Q000502:physiology; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism; D002394:Catechol O-Methyltransferase / Q000235:genetics; D050483:Dopamine Plasma Membrane Transport Proteins / Q000235:genetics; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D011618:Psychotic Disorders / Q000000981:diagnostic imaging / Q000235:genetics* / Q000523:psychology*; D017448:Receptors, Dopamine D2 / Q000235:genetics* / Q000378:metabolism*; D050638:Receptors, Dopamine D4 / Q000235:genetics; D012559:Schizophrenia / Q000000981:diagnostic imaging / Q000235:genetics* / Q000378:metabolism; D012565:Schizophrenic Psychology; D035781:Siblings; D055815:Young Adult
chemical_list: C581293:DRD2 protein, human; C493599:DRD4 protein, human; D050483:Dopamine Plasma Membrane Transport Proteins; D017448:Receptors, Dopamine D2; C493214:SLC6A3 protein, human; D050638:Receptors, Dopamine D4; C588010:COMT protein, human; D002394:Catechol O-Methyltransferase
keywords: Anhedonia; Dopamine; Genetic profile; Negative symptoms; PET; Schizophrenia