A Genetic Study of Psychosis in Huntington’s Disease: Evidence for the Involvement of Glutamate Signaling Pathways

Article type: Research Article

Authors: Tsuang, Debby W.^{a; b; c; 1; *} | Greenwood, Tiffany A.^{d; 1} | Jayadev, Suman^e | Davis, Marie^{a; e} | Shutes-David, Andrew^{a; f} | Bird, Thomas D.^{a; c; e}

Affiliations: [a] Geriatric Research, Education, and Clinical Center, VA Puget Sound Health Care System, Seattle, WA, USA | [b] Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA, USA | [c] Department of Medicine, Division of Medical Genetics, University of Washington, Seattle, WA, USA | [d] Department of Psychiatry, University of California San Diego, La Jolla, CA, USA | [e] Department of Neurology, University of Washington, Seattle, WA, USA | [f] Mental Illness Research, Education, and Clinical Center, VA Puget Sound Health Care System, Seattle, WA, USA

Correspondence: [*] Correspondence to: Dr. Debby W. Tsuang, S-182 GRECC, VA Puget Sound Health Care System, 1660 S. Columbian Way, Seattle, WA 98108, USA. Tel.: +1 206 277 1333; E-mail: dwt1@uw.edu.

Note: [1] These authors contributed equally to this work.

Abstract: Background:Psychotic symptoms of delusions and hallucinations occur in about 5% of persons with Huntington’s disease (HD). The mechanisms underlying these occurrences are unknown, but the same symptoms also occur in schizophrenia, and thus genetic risk factors for schizophrenia may be relevant to the development of psychosis in HD. Objective:To investigate the possible role of genes associated with schizophrenia in the occurrence of psychotic symptoms in HD. Methods:DNA from subjects with HD and psychosis (HD+P; n = 47), subjects with HD and no psychosis (HD-P; n = 126), and controls (CTLs; n = 207) was genotyped using the Infinium PsychArray-24 v1.1 BeadChip. The allele frequencies of single-nucleotide polymorphisms (SNPs) that were previously associated with schizophrenia and related psychiatric disorders were compared between these groups. Results:Of the 30 candidate genes tested, 10 showed an association with psychosis in HD. The majority of these genes, including CTNNA2, DRD2, ERBB4, GRID2, GRIK4, GRM1, NRG1, PCNT, RELN, and SLC1A2, demonstrate network interactions related to glutamate signaling. Conclusions:This study suggests genetic associations between several previously identified candidate genes for schizophrenia and the occurrence of psychotic symptoms in HD. These data support the potential role of genes related to glutamate signaling in HD psychosis.

Keywords: Delusions, genetic association studies, genetic predisposition to disease, genetics, glutamates, hallucinations, Huntington disease, modifier genes, psychotic disorders, schizophrenia

DOI: 10.3233/JHD-170277

Journal: Journal of Huntington's Disease, vol. 7, no. 1, pp. 51-59, 2018