Genetic copy number variants in sib pairs both affected with schizophrenia

Abstract

BackgroundSchizophrenia is a complex disorder with involvement of multiple genes.MethodsIn this study, genome-wide screening for DNA copy-number variations (CNVs) was conducted for ten pairs, a total of 20 cases, of affected siblings using oligonucleotide array-based CGH.ResultsWe found negative symptoms were significantly more severe (p < 0.05) in the subgroup that harbored more genetic imbalance (n ≧ 13, n = number of CNV-disrupted genes) as compared with the subgroup with fewer CNVs (n ≦ 6), indicating that the degree of genetic imbalance may influence the severity of the negative symptoms of schizophrenia. Four central nervous system (CNS) related genes including CCAAT/enhancer binding protein, delta (CEBPD, 8q11.21), retinoid × receptor, alpha (RXRA, 9q34.2), LIM homeobox protein 5 (LHX5, 12q24.13) and serine/threonine kinase 11 (STK11, 19p13.3) are recurrently (incidence ≧ 16.7%) disrupted by CNVs. Two genes, PVR (poliovirus receptor) and BU678720, are concordantly deleted in one and two, respectively, pairs of co-affected siblings. However, we did not find a significant association of this BU678720 deletion and schizophrenia in a large case-control sample.ConclusionsWe conclude that the high genetic loading of CNVs may be the underlying cause of negative symptoms of schizophrenia, and the CNS-related genes revealed by this study warrant further investigation.

Psychosis in Alzheimer’s Disease

“…Although STK11 deletions are present in Peutz-Jeghers syndrome, one case with an unusually large STK11 deletion has been described in which Peutz-Jeghers syndrome, mental retardation, and schizophrenia co-occurred (50). Similarly, a genome-wide screen in siblings co-affected by schizophrenia found reduced copy numbers of STK11 in 3 of 18 individuals, significantly more often than in control subjects (51). Of interest, STK11, also known as liver kinase B1, triggers phosphorylation of tau (52), and amyloid precursor protein overexpression promotes tau phosphorylation in an liver kinase B1-dependent manner (53).…”

C/EBPβ and C/EBPδ transcription factors: Basic biology and roles in the CNS

“…Large CNVs containing CEBPB or CEBPD and hundreds of genes have been associated as pathogenic for developmental delay phenotypes, but smaller CNVs-containing regions with only the CEBPB or CEBPD genes and few adjacent genes are not suspected to be pathogenic (Kaminsky et al 2011). One study has reported frequent loss of one allele (hemizygosis) in the CEBPD locus in familiar schizophrenia patients (Lee et al 2010a). Gene copy amplification of CEBPD has been associated with glioblastoma ) and loss of heterozygosity in a region containing the CEBPD gene in one patient with atherosclerosis (Sleptsov et al 2014).…”

Gene expression profiling of the dorsolateral and medial orbitofrontal cortex in schizophrenia

“…Moreover, RNA sequencing can quantify the transcripts with an absolute number value, rather than yielding a relative value as in microarray. Other research has suggested, even though relatively uncommon, that copy number variation (CNV) deletions or replications can lead to variable gene expression and cause schizophrenia with symptoms of differing severity [77, 78]. Thus, one of the limitations of our study is that, by using a RNA microarray, these CNV could not be detected.…”