title: Schizophrenia-like neurophysiological abnormalities in 22q11.2 deletion syndrome and their association to COMT and PRODH genotypes.
abstract: 22q11.2 deletion syndrome (22q11.2DS) is a common genetic risk factor for the development of schizophrenia. We investigated two neurophysiological endophenotypes of schizophrenia - P50 sensory gating and mismatch negativity in 22q11.2DS subject and evaluated their association with catechol O-methyltransferase (COMT) and proline dehydrogenase (PRODH) genetic variants. We also assessed the association of neurophysiological measures with schizophrenia-like symptomatology in 22q11.2DS. Fifty-nine subjects, 41 with 22q11.2DS and 18 typically developing controls, participated in the study. The participants with 22q11.2DS were genotyped for the COMT Val(158)Met (rs4680) and PRODH Gln(19)Pro (rs2008720) and Arg(185)Trp (rs4819756) polymorphisms. Following psychiatric evaluation, all the participants underwent neurophysiological recordings and executive function assessment. The 22q11.2DS group showed poorer sensory gating of the P50 response than the controls. Within the 22q11.2DS group, the COMT Met allele was associated with poorer sensory gating, while both the COMT Met allele and the PRODH Pro-Arg haplotype were associated with smaller mismatch negativity amplitudes. Smaller mismatch negativity amplitudes predicted greater impairment of executive functions and greater severity of schizophrenia-like negative symptoms in 22q11.2DS. The current study demonstrates that sensory gating impairments that are typical of schizophrenia are found in 22q11.2DS subjects. Our results further suggest that COMT and PRODH genetic variations contribute to sensory gating and mismatch negativity schizophrenia-like impairments in 22q11.2DS, possibly via dopaminergic/glutamatergic networks. The associations of mismatch negativity impairments with increased severity of schizophrenia-like negative symptoms and poorer executive functions performance in our 22q11.2DS sample suggest that mismatch negativity is a potential endophenotype for schizophrenia in 22q11.2DS.
authors.affiliation: The Behavioral Neurogenetics Center, The Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel Hashomer 52621, Israel; The Institute for Clinical Neurophysiology and Audiology, Rabin Medical Center, Petah Tikva 49202, Israel; The Interdisciplinary Ph.D. Program in Neuroscience, Tel Aviv University, Tel Aviv 69978, Israel. Electronic address: omerz@post.tau.ac.il.
authors.forename: Omer
authors.initials: O
authors.lastname: Zarchi
authors.forename: Miri
authors.initials: M
authors.lastname: Carmel
authors.forename: Chen
authors.initials: C
authors.lastname: Avni
authors.forename: Josef
authors.initials: J
authors.lastname: Attias
authors.forename: Amos
authors.initials: A
authors.lastname: Frisch
authors.forename: Elena
authors.initials: E
authors.lastname: Michaelovsky
authors.forename: Miriam
authors.initials: M
authors.lastname: Patya
authors.forename: Tamar
authors.initials: T
authors.lastname: Green
authors.forename: Ronnie
authors.initials: R
authors.lastname: Weinberger
authors.forename: Abraham
authors.initials: A
authors.lastname: Weizman
authors.forename: Doron
authors.initials: D
authors.lastname: Gothelf
mesh_terms: D058165:22q11 Deletion Syndrome / Q000235:genetics* / Q000503:physiopathology*; D000161:Acoustic Stimulation; D000293:Adolescent; D000328:Adult; D002394:Catechol O-Methyltransferase / Q000235:genetics*; D002648:Child; D003265:Contingent Negative Variation / Q000235:genetics; D058068:Endophenotypes; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008297:Male; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011394:Proline Oxidase / Q000235:genetics*; D012559:Schizophrenia / Q000503:physiopathology*; D055139:Sensory Gating / Q000235:genetics; D055815:Young Adult
chemical_list: D011394:Proline Oxidase; C582834:PRODH protein, human; D002394:Catechol O-Methyltransferase
keywords: 22q11.2DS; Catechol O-methyltransferase; Endophenotype; Mismatch negativity; Proline dehydrogenase; Sensory gating