Analysis of Rare and Novel Gene Variants in Schizophrenia and Dementia

Rare and damaging variants have been newly discovered in 18 genes of patients who were Mexican with extreme phenotypes of schizophrenia or late-onset Alzheimer dementia, according to a study published in Revista de Investigación Clínica [Journal of Clinical Investigation]. A possible link between cognitive impairment and psychosis was also discovered via a variation on the ATP binding cassette subfamily C member 1 gene. The researchers caution that all discoveries should be corroborated through research with larger sample sizes.

Schizophrenia and dementia are among the most common neuropsychiatric diseases. Compared with individuals without schizophrenia, people with schizophrenia have a 2-fold risk for dementia, but the etiology of these complex diseases has yet to be fully elucidated. Although genome-wide association studies (GWAS) have explained approximately 12% of the phenotypic variation, there is an apparent missing heritability, which could potentially be found by using next-generation sequencing to investigate rare, highly damaging and novel variants not routinely included in GWAS analyses. The current study was designed to do this in 184 genes in 19 patients (n=7 for late-onset dementia of Alzheimer type, and n=12 for schizophrenia) being treated at the Group of Medical and Family Studies Carracci and the Geriatric Clinic at the Psychiatric Hospital “Fray Bernardino Alvarez” in Mexico City, Mexico, between 2011 and 2013.

Analyses detected 1274 variants in the 184 genes. In 3 of the 7 patients with dementia (42.9%), 5 damaging variants were detected in 5 genes (neurexin 1; 5-hydroxytryptamine receptor 1A; potassium voltage-gated channel subfamily H member 2; carbonyl reductase 1; and ATP binding cassette subfamily C member 1); novel or loss-of-function (LoF) variants were not observed. One patient with dementia carried 3 of the 7 damaging variations on neurexin 1; potassium voltage-gated channel subfamily H member 2; and ATP binding cassette subfamily C member 1; and this patient scored lowest in the mini-mental state examination, demonstrating that the patient’s condition affected almost all of his cognitive areas. Among the patients with schizophrenia, 13 variants were detected on 13 genes

• ankyrin 2;
• cytochrome P450 family 3 subfamily A member 4;
• reelin;
• 5-hydroxytryptamine receptor 7;
• DISC1 scaffold protein;
• thymidylate synthetase;
• cytochrome P450 family 2 subfamily B member 6;
• methylenetetrahydrofolate reductase;
• neuregulin 1;
• solute carrier family 6 member 5;
• brain derived neurotrophic factor;
• glutamate ionotropic receptor NMDA type subunit 2B; and
• ATP binding cassette subfamily C member 1.

Of these genes, 4 were LoF variants on ankyrin 2; cytochrome P450 family 3 subfamily A member 4; reelin; and 5-hydroxytryptamine receptor 7. Six novel variants were identified, representing almost half of all the gene variants detected in these patients. Ten of the 12 patients with schizophrenia (83.33%) were carriers of a damaging variant. The patient carrying the LoF in cytochrome P450 family 3 subfamily A member 4 gene had treatment-resistant schizophrenia, and the patient carrying the variants on the DISC1 scaffold protein gene had the lowest cognitive function scores on the mini-mental state examination.

Study investigators concluded that they found rare and novel damaging variants on 18 genes in this population of patients, including variants that may be linked to cognitive decline and treatment-resistant schizophrenia. In addition, they pointed to a variation on the ATP binding cassette subfamily C member 1 gene that could be a link between psychosis and cognitive impairment. However, they also stressed that this study should be viewed as an exploratory analysis, and the findings should be corroborated in research studies with larger sample sizes.

Reference

Martínez-Magaña JJ, Genís-Mendoza AD, González-Covarrubias V, et al. Exploratory analysis of rare and novel variants in Mexican patients diagnosed with schizophrenia and dementia. Rev Invest Clin. 2019;71(4):246-254.