Schizophrenia-like neurophysiological abnormalities in 22q11.2 deletion syndrome and their association to COMT and PRODH genotypes

Omer Zarchi; Miri Carmel; Chen Avni; Josef Attias; Amos Frisch; Elena Michaelovsky; Miriam Patya; Tamar Green; Ronnie Weinberger; Abraham Weizman; Doron Gothelf

doi:10.1016/j.jpsychires.2013.07.004

Schizophrenia-like neurophysiological abnormalities in 22q11.2 deletion syndrome and their association to COMT and PRODH genotypes

J Psychiatr Res. 2013 Nov;47(11):1623-9. doi: 10.1016/j.jpsychires.2013.07.004. Epub 2013 Aug 1.

Authors

Omer Zarchi¹, Miri Carmel, Chen Avni, Josef Attias, Amos Frisch, Elena Michaelovsky, Miriam Patya, Tamar Green, Ronnie Weinberger, Abraham Weizman, Doron Gothelf

Affiliation

¹ 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.

PMID: 23910792
DOI: 10.1016/j.jpsychires.2013.07.004

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.

Keywords: 22q11.2DS; Catechol O-methyltransferase; Endophenotype; Mismatch negativity; Proline dehydrogenase; Sensory gating.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

22q11 Deletion Syndrome / genetics*
22q11 Deletion Syndrome / physiopathology*
Acoustic Stimulation
Adolescent
Adult
Catechol O-Methyltransferase / genetics*
Child
Contingent Negative Variation / genetics
Endophenotypes
Female
Genetic Association Studies
Genetic Predisposition to Disease
Genotype
Humans
Male
Polymorphism, Single Nucleotide / genetics*
Proline Oxidase / genetics*
Schizophrenia / physiopathology*
Sensory Gating / genetics
Young Adult

Substances

Proline Oxidase
PRODH protein, human
Catechol O-Methyltransferase