Identification of rare copy number variants in high burden schizophrenia families

Abstract

Over the last years, genome-wide studies consistently showed an increased burden of rare copy number variants (CNVs) in schizophrenia patients, supporting the "common disease, rare variant" hypothesis in at least a subset of patients. We hypothesize that in families with a high burden of disease, and thus probably a high genetic load influencing disease susceptibility, rare CNVs might be involved in the etiology of schizophrenia. We performed a genome-wide CNV analysis in the index patients of eight families with multiple schizophrenia affected members, and consecutively performed a detailed family analysis for the most relevant CNVs. One index patient showed a DRD5 containing duplication. A second index patient presented with an NRXN1 containing deletion and two adjacent duplications containing MYT1L and SNTG2. Detailed analysis in the subsequent families showed segregation of the identified CNVs. With this study we show the importance of screening high burden families for rare CNVs, which will not only broaden our knowledge concerning the molecular genetic mechanisms involved in schizophrenia but also allow the use of the obtained genetic data to provide better clinical care to these families in general and to non-symptomatic causal CNV carriers in particular.

Olanzapine induced DNA methylation changes support the dopamine hypothesis of psychosis

“…Furthermore, DRD1 and DRD5 have been reported to have distinct regulatory roles on synaptic plasticity, spontaneous motor activity, memory and the information being processed by the hippocampus [31, 32]. Here we show that DRD5 , which encodes the D5 subtype DA receptor, and has been previously described as a susceptibility gene for schizophrenia [33, 34], may result in diminished D5 subtype by increase in methylation following olanzapine treatment. This is expected in all three tissues studied.…”

Copy number variants analysis in a cohort of isolated and syndromic developmental delay/intellectual disability reveals novel genomic disorders, position effects and candidate disease genes

“…One case with a CNV inherited from an affected parent is a 360‐kb long, paternally transmitted duplication spanning DRD5 and two other genes in a case with DD/ID (case 299797). The rearrangement overlaps with a larger duplication described in 6 related individuals, 4 of which had schizophrenia or schizoaffective disorder (the remaining 2 subjects were under the average age of onset in this family) …”

Genetic Associations with Plasma B12, B6, and Folate Levels in an Ischemic Stroke Population from the Vitamin Intervention for Stroke Prevention (VISP) Trial

“…Although we did not observe any genome-wide significant associations for folate, we did detect suggestive evidence for association ( P  = 9.75 × 10 −07 ) near the MYT1L gene, located on chromosome 2. Interestingly, genetic variations at this locus have been associated with depression (32) and schizophrenia (33–35). This locus may help explain the recent data positively correlating serum folate levels with cognitive test scores in children (36); suggesting further evaluation of the effects of folate levels in the elderly are warranted.…”